CN117715904A - CDK2 degraders and their uses - Google Patents

Abstract

The present invention provides compounds, compositions thereof, and methods of use.

Description

CDK2 degraders and uses thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Application No. 63/185,929, filed on May 7, 2021, the entire contents of which are incorporated herein by reference.

Technical Field

The present invention relates to compounds useful for regulating cyclin-dependent kinase 2 ("CDK2") proteins via ubiquitination and/or degradation, and methods of regulating cyclin-dependent kinase 2 ("CDK2") proteins via ubiquitination and/or degradation using compounds according to the present invention. The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using the compositions to treat various disorders.

Background Art

The ubiquitin-proteasome pathway (UPP) is a key pathway for regulating key regulatory proteins and degrading misfolded or abnormal proteins. The UPP is central to multiple cellular processes and, if deficient or unbalanced, it contributes to the pathogenesis of a variety of diseases. Covalent attachment of ubiquitin to specific protein substrates is achieved via the action of E3 ubiquitin ligases.

There are more than 600 E3 ubiquitin ligases that promote the in vivo ubiquitination of different proteins, which can be divided into four families: HECT-domain E3, U-box E3, monomeric RING E3 and multi-subunit E3. See generally Li et al. (PLOS One, 2008, 3, 1487), entitled "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling"; Berndsen et al. (Nat. Struct. Mol. Biol., 2014, 21, 301-307), entitled "New insights into the mechanism of ubiquitin E3 ligases Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434), entitled “RINGdomain E3 ubiquitin ligases”; Spratt et al. (Biochem. 2014, 458, 421-437), entitled “RBR E3 ubiquitin ligases: new structures, new insights, new questions”; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347), entitled “Roles of F-box proteins in cancer”.

UPP is used to induce selective protein degradation, including artificial ubiquitination of target proteins and synthetic small molecule probes using fusion proteins to induce proteasome-dependent degradation. The bifunctional compound consisting of a ligand and an E3 ubiquitin ligase ligand that binds to the target protein induces proteasome-mediated degradation of the selected protein by recruiting the selected protein to the E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules make it possible to temporarily control protein expression. Such compounds can induce the inactivation of the protein of interest when added to cells or administered to animals or humans, and can be used as biochemical reagents and produce a new paradigm for treating diseases by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17 (6): 551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6 (l): 40-46).

There is still a continuing need in the art for effective treatment of diseases, especially cancer. Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases. After heterodimerization with regulatory subunits called cyclins, such as cyclin E1 ("CCNE1"), CDKs are fully activated and regulate key cellular processes, including cell cycle progression and cell division. Uncontrolled proliferation is a hallmark of cancer cells. Disorders of CDK activity are associated with abnormal regulation of the cell cycle and have been detected in almost all forms of human cancer. Therefore, small molecule therapeutics that make full use of UPP-mediated protein degradation to target cancer-related proteins, such as cyclin-dependent kinase 2 ("CDK2") or CDK2 and CCNE1 proteins, are expected to become therapeutic agents. Therefore, there is still a need to find compounds that are CDK2 or CDK2 and CCNE1 degraders suitable for use as therapeutic agents.

Summary of the invention

The present application relates to novel bifunctional compounds for recruiting CDK2 or CDK2 and CCNE1 proteins to E3 ubiquitin ligases for degradation, and methods for preparing and using the same. Specifically, the present disclosure provides bifunctional compounds that are suitable for use as modulators of targeted ubiquitination of CDK2 or CDK2 and CCNE1, which are subsequently degraded and/or otherwise inhibited by bifunctional compounds as described herein. Monovalent compounds are also provided that are suitable for use as inducers of targeted ubiquitination of CDK2 or CDK2 and CCNE1, which are subsequently degraded and/or otherwise inhibited by monovalent compounds as described herein. The advantage of the compounds provided herein is that a wide range of pharmacological activities are possible, consistent with the degradation/inhibition of CDK2 or CDK2 and CCNE1. In addition, embodiments provide methods of using an effective amount of a compound as described herein to treat or alleviate a disease condition, such as a disease condition caused by abnormal CDK2 or CDK2 and CCNE1 activity.

The present application further relates to targeted degradation of CDK2 or CDK2 and CCNE1 proteins through the use of bifunctional molecules comprising linking a cereblon binding moiety to a bifunctional molecule that binds a ligand that binds CDK2 or CDK2 and CCNE1.

It has been found that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as degraders of CDK2 or CDK2 and CCNE1 proteins. The compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for treating a variety of diseases, disorders or conditions associated with the regulation of CDK2 proteins. Such diseases, disorders or conditions include those described herein.

The compounds provided by the present invention are also suitable for studying CDK2 proteins in biological and pathological phenomena; and for comparative evaluation of novel CDK2 inhibitors or CDK2 degraders in vitro or in vivo.

DETAILED DESCRIPTION

1. General Description of Certain Embodiments of the Invention:

The compounds of the present invention and their compositions are useful as degraders and/or inhibitors of CDK proteins. In some embodiments, the compounds provided degrade and/or inhibit CDK2 proteins. In some embodiments, the compounds provided degrade and/or inhibit CDK2 and CCNE1 proteins.

In certain embodiments, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

CBM is a CDK binding portion capable of binding CDK2 or CDK2 and CCNE1;

L is a divalent moiety linking CBM to DIM; and

DIM is a degradation inducing moiety, such as a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.

2. Compounds and definitions:

The compounds of the present invention include those compounds generally described herein and further described by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; and "March's Advanced Organic Chemistry", 5th edition, eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., non-branched chain) or branched substituted or unsubstituted hydrocarbon chain that is completely saturated or contains one or more unsaturated units, or a monocyclic, bicyclic, bridged bicyclic or spirocyclic hydrocarbon that is completely saturated or contains one or more unsaturated units but is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic group" or "cycloalkyl"), which has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic _C3 - _C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight or branched chain, substituted or unsubstituted alkyl, alkenyl, alkynyl, and mixed groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

As used herein, the term "bridged bicyclic" refers to any bicyclic system with at least one bridge, i.e., a carbocyclic or heterocyclic, saturated or partially unsaturated bicyclic system. As defined by IUPAC, a "bridge" is an unbranched chain of multiple atoms or an atom or a valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom of a ring system bonded to three or more backbone atoms (except hydrogen). In some embodiments, the bridged bicyclic group has 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, the bridged bicyclic group is optionally substituted with one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

The term "lower alkyl" refers to a C _1-4 straight or branched chain alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

The term "lower haloalkyl" refers to a C _1-4 straight or branched chain alkyl group substituted by one or more halogen atoms.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; a quaternized form of any base nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl)).

As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

As used herein, the term "divalent C _1-8 (or C _1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains that are straight or branched as defined herein.

The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH ₂ ) _n -, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

As used herein, the term "cyclopropylene" refers to a divalent cyclopropyl radical of the following structure:

The term "halogen" means F, Cl, Br or I.

The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkyloxy" or "aryloxyalkyl", refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc., which may carry one or more substituents. As used herein, also included within the scope of the term "aryl" are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, etc.

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6 or 9 ring atoms, sharing 6, 10 or 14 π electrons in the cyclic array, and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of the base nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaryl-" also include groups in which a heteroaryl ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the linker or point of attachment is on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, oxazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenathiazinyl, phenoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group may be monocyclic or bicyclic. The heteroaryl ring may include one or more oxo (=O) or thionyl (=S) substituents. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which include optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions are independently optionally substituted.

As used herein, the terms "heterocycle" and "heterocyclic ring" and "heterocyclyl" and "heterocyclic radical" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used with respect to the ring atoms of the heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or ⁺ NR (as in N-substituted pyrrolidinyl).

The heterocycle can be connected to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, oxazolidinyl, piperazinyl, dioxane, dioxolane, diazepine, oxazepine, thiazepine, morpholinyl and quinuclidine. The terms "heterocycle", "heterocyclic radical", "heterocyclic group" and "heterocyclic moiety" are used interchangeably herein, and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolyl. The heterocyclic group can be a monocyclic, bicyclic, bridged bicyclic or spirocyclic ring. The heterocycle may include one or more oxo (=O) or thioketo (=S) substituents. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties as defined herein.

As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens in the specified moiety are replaced with suitable substituents. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combinations of substituents contemplated by the present invention are preferably those combinations of substituents that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" means that a compound does not undergo substantial changes when subjected to conditions that allow its production, detection, and (in certain embodiments) its recovery, purification, and use for one or more purposes disclosed herein.

Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently halogen; -(CH ₂ ) _0-4 R ^o ; -(CH ₂ ) _0-4 OR ^o ; -O(CH ₂ ) _0-4 R ^o ; -O-(CH ₂ ) _0-4 C(O)OR ^{o ;} -(CH ₂ ) _0-4 CH(OR ^o ) ₂ ; -(CH ₂ ) _0-4 SR ^o ; -(CH ₂ ) _0-4 Ph which may be substituted by R ^o ; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph which may be substituted by R ^o ; -CH═CHPh which may be substituted by R ^o ; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl which may be substituted by R ^o ; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _0-4 N(R ^o ) ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)R ^o ;-N(R ^o )C(S)R ^o ;-(CH ₂ ) _0-4 N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )C(S)NR ^o ₂ ;-(CH ₂ ) _0-4 N(R ^o )C(O)OR ^o ;-N(R ^o )N( R ^o )C(O)R ^o ;-N(R ^o )N(R ^o )C(O)NR ^o ₂ ;-N(R ^o )N(R ^o )C(O)OR ^o ;-(CH ₂ ) _0-4 C(O)R ^o ;-C(S)R ^o ;-(CH ₂ ) _{0- 4} C(O)OR ^o ;-(CH ₂ ) _-C (S)SR ^o ; _-SC (S) _{SR o} ;-(CH _{2 ) 0-4} OC(O)NR ^o _{2 ;} -C(O)N ₍ OR o ) ^{R o} ; _-C (O)C( ^O ) ^{R o} _{; -C} (O) ^CH ₂ C(O) ^{R o ;} _-C ( ^{NOR o} ) ^{R o ;-(} _{CH 2 ) 0-4 SSR} ^o ;-( ^CH ₂ ) _0-4 S(O) ₂ R ^o ;-(CH ₂ ) _0-4 S(O) ₂ OR ^o ;-(CH ₂ ) _0-4 OS(O) ₂ R ^o ;-S(O) ₂ NR ^o ₂ ;-(CH ₂ ) _0-4 S(O)R ^o ;-N(R ^o )S(O) ₂ NR ^o ₂ ;-N(R ^o )S(O) ₂ R ^o ;-N (OR ^o )R ^o ; -C(NH)NR ^o ₂ ; -P(O) ₂ R ^o ; -P(O)R ^o ₂ ; -OP(O)R ^o ₂ ; -OP(O)(OR ^o ) ₂ ; SiR ^o ₃ ; -(C _1-4 linear or branched chain alkylene)ON(R ^o ) ₂ ; or -(C wherein each R ^o may be substituted as defined below and is independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 ^Ph , -CH ₂ -( _{5-6 membered heteroaryl ring) or a 5-6 membered} saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definition, two independent occurrences of R ^o together with their one or more intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R ^o (or two individual occurrences of R ^o together with their intervening atoms to form a ring) are independently halogen, -(CH ₂ ) _0-2 R ^● , -(halo R ^● ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^● , -(CH ₂ ) _0-2 CH(OR ^● ) ₂ , -O(halo R ^● ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^● , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^● , -(CH ₂ ) _0-2 SR ^● , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^● , _- (CH ₂ ) 0-2 _0-2 NR ^● ₂ , -NO ₂ , -SiR ^● ₃ , -OSiR ^● ₃ , -C(O)SR ^● , -(C _1-4 straight or branched alkylene)C(O)OR ^● or -SSR ^● , wherein each R ^● is unsubstituted or, when crowned with "halo", is substituted only with one or more halogens, and is independently selected from C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) _2R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3O- , or -S(C(R ^* ₂ )) _2-3S- , wherein R ^* at each separate occurrence is selected from hydrogen, a _C1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents bonded to an ortho-substitutable carbon of an "optionally substituted" group include: -O(CR ^* ₂ ) _2-3 O-, wherein R ^* at each separate occurrence is independently selected from hydrogen, a C _1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of R ^* include halogen, -R ^● , -(halo R ^● ), -OH, -OR ^● , -O(halo R ^● ), -CN, -C(O)OH, -C(O)OR ^● , -NH ₂ , -NHR ^● , -NR ^● ₂ or -NO ₂ , wherein each R ^● is unsubstituted or, when prefixed with "halo", is substituted only with one or more halogens, and is independently a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of is independently hydrogen, C _1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of Together with its one or more intervening atoms, it forms an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group include halogen, -R ^● , -(haloR ^● ), -OH, -OR ^● , -O(haloR ^● ), -CN, -C(O)OH, -C(O)OR ^● , -NH ₂ , -NHR ^● , -NR ^● ₂ or -NO ₂ , wherein each R ^● is unsubstituted or, when prefixed with "halo", is substituted only with one or more halogens, and is independently a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6-membered saturated, partially unsaturated or aromatic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and are commensurate with a reasonable benefit/risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences), 1977, 66, 1-19, which are incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of amino groups with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), or salts formed by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, low carbon alkyl sulfonates, and aryl sulfonates. In some embodiments, the provided compounds are purified in salt form for convenience and/or ease of purification, such as using an acidic or basic mobile phase during chromatography. The salt forms of the provided compounds formed during chromatographic purification are contemplated herein and are apparent to those skilled in the art.

Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or configurational)) forms of the structure; for example, R and S configurations, Z and E double bond isomers, and Z and E configurational isomers for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or configurational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise stated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention, including replacement of hydrogen by deuterium or tritium or replacement of carbon by ¹³ C or ¹⁴ C-enriched carbon, are within the scope of the invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the invention.

As used herein, the term "provided compounds" refers to any genus, subgenus, and/or species described herein.

As used herein, the term "inhibitor" is defined as a compound that binds to and/or inhibits CDK2 or CDK2 and CCNE1 with measurable affinity. In certain embodiments, the inhibitor has an IC ₅₀ and/or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

As used herein, the term "degrader" is defined as a heterobifunctional compound that binds to and/or inhibits both CDK2 or CDK2 and CCNE1 and an E3 ligase with measurable affinity, thereby causing ubiquitination and subsequent degradation of CDK2 or CDK2 and CCNE1. In certain embodiments, the DC ₅₀ of the degrader is less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. As used herein, the term "monovalent" refers to a degrader compound without an additional E3 ligase binding moiety.

The compounds of the present invention can be tethered to a detectable portion. It should be understood that such compounds are suitable for use as developer. A person of ordinary skill in the art will recognize that a detectable portion can be connected to a provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a portion that can be covalently attached to a detectable portion. Such portions are well known to those of ordinary skill in the art and include groups containing, for example, carboxylate moieties, amino moieties, thiol moieties, or hydroxyl moieties (to name a few). It should be understood that such portions can be directly or via a tethered group (such as a divalent saturated or unsaturated hydrocarbon chain) connected to a provided compound. In some embodiments, such portions can be connected via click chemistry. In some embodiments, such portions can be connected via 1,3-cycloaddition of azide and alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety capable of detection, such as primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, ³² P, ³³ P, ³⁵ S or ¹⁴ C), mass labels, and fluorescent labels are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to produce a detectable signal. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. In the case of antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups serve as secondary labels because they transfer energy to another group in a non-radiative fluorescence resonance energy transfer (FRET) method, and the second group produces a detected signal.

[0063] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530/550, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY 630/650, BODIPY 650/665), Carboxyrhodamine 6G ( 6G), carboxy-X-rhodamine (ROX), CascadeBlue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, dialkylaminocoumarins, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, hydroxycoumarins, IRDye (IRD40, IRD 700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthylfluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue Blue), PyMPO, pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

As used herein, the term "mass tag" refers to any moiety that can be uniquely detected by means of its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretically released tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceryl]isopicolinic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and its derivatives. The synthesis and utility of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying lengths and base compositions; oligopeptides, oligosaccharides and other synthetic polymers of varying lengths and monomer compositions. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds), with an appropriate mass range (100 to 2000 Daltons) can also be used as mass tags.

As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in CDK2 or CDK2 and CCNE1 activity between a sample comprising a compound of the invention, or composition thereof, and CDK2 or CDK2 and CCNE1 and an equivalent sample comprising CDK2 or CDK2 and CCNE1 but without the compound or composition thereof.

3. Description of exemplary embodiments:

As described above, in certain embodiments, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

CBM is a CDK binding portion capable of binding CDK2 or CDK2 and CCNE1;

L is a divalent moiety linking CBM to DIM; and

DIM is a degradation inducing moiety, such as a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom.

CDK2 Binding Moiety (CBM)

As defined herein and described above, CBM is a CDK binding portion capable of binding to CDK2 protein. In some embodiments, CBM binds to CDK2 protein, which then undergoes ubiquitination, thereby marking CDK2 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, CBM is a CDK binding portion capable of selectively binding and degrading CDK2 relative to other CDK proteins (e.g., CDK1, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, etc.). In some embodiments, CBM is a CDK binding portion capable of selectively binding and degrading CDK2 relative to one or more of CDK1, CDK4, and CDK9 proteins.

In some embodiments, the CBM binds to CDK2 and CCNE1 proteins, which subsequently undergo ubiquitination, thereby marking CDK2 and CCNE1 for degradation via the ubiquitin-proteasome pathway (UPP). In some embodiments, provided compounds are dual CDK2 and CCNE1 degraders.

As defined herein and described below, where square brackets are used to delineate a formula, e.g. L is attached to a modifiable carbon, oxygen, or nitrogen atom within the CBM, including substitution or replacement of defined groups in the CBM.

In certain embodiments, the present invention provides compounds of Formula I, wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, thereby forming a compound of Formula I-a:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein:

R ^a and R ^b are independently hydrogen or R ^A , or

^Ra and ^Rb together with the nitrogen to which they are attached form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached;

each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring W, Ring X and Ring Y are independently selected from the following rings: phenyl, 4-7 membered saturated or partially unsaturated carbocyclic group or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-;

v is 0 or 1; and

w, x, y and z are independently 0, 1, 2, 3 or 4.

In certain embodiments, the present invention provides compounds of Formula I, wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, thereby forming a compound of Formula I-b:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein:

Ring W and Ring X are independently a fused ring selected from the following: benzo, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Y is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; or

Two R ^w groups attached to the same carbon atom optionally together form a spiro-fused ring selected from: 3-5 membered saturated or partially unsaturated carbocyclyl and 3-5 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen optionally take together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-;

v is 0 or 1; and

w, x, y and z are independently 0, 1, 2, 3 or 4.

In certain embodiments, the present invention provides compounds of Formula I, wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, thereby forming a compound of Formula I-c:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein:

Ring W, Ring X and Ring Y are independently selected from the following rings: phenyl, 4-7 membered saturated or partially unsaturated carbocyclic group or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R;

each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-;

v is 0 or 1; and

w, x, y and z are independently 0, 1, 2, 3 or 4.

In certain embodiments, the present invention provides compounds of Formula I, wherein the CBM is a CDK2 or CDK2 and CCNE1 binding moiety, thereby forming a compound of Formula I-d:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein:

R ^a and R ^b are independently hydrogen or R ^A , or

^Ra and ^Rb together with the nitrogen to which they are attached form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached;

each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring W is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring X is a bicyclic ring selected from naphthyl, a 9- to 10-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 9- to 10-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ^w , R ^x and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S (O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC(O) R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O) (OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R ,-NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-;

v is 0 or 1; and

w, x and z are independently 0, 1, 2, 3 or 4.

In certain embodiments, the present invention provides compounds of Formula I, wherein the CBM is a CDK2 or a CDK2 and CCNE1 binding moiety, thereby forming a compound of Formula I-e:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described herein, and wherein:

Ring W and Ring X are independently a ring selected from the following: phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Y is a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; or

Two R ^w groups attached to the same carbon atom optionally together form a spiro-fused ring selected from: 3-5 membered saturated or partially unsaturated carbocyclyl and 3-5 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur;

each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen optionally take together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

^Lx and ^Ly are independently a covalent bond or a _C1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, _-CF2- , -CRF-, -NR-, -S-, -S(O)-, -S(O) _2- , or -CR=CR-;

v is 0 or 1; and

w, x, y and z are independently 0, 1, 2, 3 or 4.

As generally defined above, ^Ra and ^Rb are independently hydrogen or ^RA , or ^Ra and ^Rb, taken together with the nitrogen to which they are attached, form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^Ra is hydrogen. In some embodiments, ^Ra is ^RA . In some embodiments, ^Rb is hydrogen. In some embodiments, ^Rb is ^RA . In some embodiments, ^Ra and ^Rb, together with the nitrogen to which they are attached, form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^Ra is isopropyl. In some embodiments, ^Ra and ^R together form

In some embodiments, ^Ra and ^Rb are selected from those depicted in Table 1 below.

As generally defined above, each ^RA is independently an optionally substituted group selected from _C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^RA is an optionally substituted C _1-6 aliphatic group. In some embodiments, R is a C _1-6 alkyl group (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is a C _1-6 haloalkyl group (e.g., -CF ₃ , CHF ₂ , etc.). In some embodiments, ^RA is an optionally substituted phenyl group. In some embodiments, ^RA is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ^RA is an optionally substituted heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RA is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, each ^RA is selected from those depicted in Table 1 below.

As generally defined above, Ring W, Ring X and Ring Y are independently a ring selected from phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclyl or a heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, one or more of ring W, ring X, and ring Y is a ring selected from phenyl. In some embodiments, one or more of ring W, ring X, and ring Y is a 4-7 membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, one or more of ring W, ring X, and ring Y is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As generally defined above, Ring W and Ring X are independently a fused ring selected from benzo, 4-7 membered saturated or partially unsaturated carbocyclyl or heterocyclyl having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, one or more of Ring W and Ring X is benzo. In some embodiments, one or more of Ring W and Ring X is a fused 4-7 membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, one or more of Ring W and Ring X is a fused 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

As generally defined above, Ring X is a bicyclic ring selected from naphthyl, a 9- to 10-membered saturated or partially unsaturated carbocyclyl or a heterocyclyl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 9- to 10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ring X is naphthyl. In some embodiments, ring X is a 9-10 membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring X is a 9-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ring W is cyclopentyl. In some embodiments, ring W is cyclohexyl. In some embodiments, ring W is In some embodiments, ring W is In some embodiments, ring W is In some embodiments, ring W is

In some embodiments, ring W is In some embodiments, ring W is In some embodiments, ring W is In some embodiments, ring W is In some embodiments, ring W is

In some embodiments, ring X is In some embodiments, ring X is In some embodiments, ring X is

In some embodiments, ring X is In some embodiments, ring X is In some embodiments, ring X is In some embodiments, ring X is

In some embodiments, Ring W, Ring X, and Ring Y are selected from those depicted in Table 1 below.

As generally defined above, Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ring Z is phenyl. In some embodiments, ring Z is a 4-8 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic radical. In some embodiments, ring Z is a 4-8 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic heterocyclic radical having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ring Z is cyclohexane.

In some embodiments, Ring Z is selected from those depicted in Table 1 below.

As generally defined above, ^Rw , ^Rx , ^Ry and ^Rz are independently selected from hydrogen, ^RA , halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , _-SiR3 , _-S (O) _2R , -S(O) _2NR2 , -S(O)R, -C(O)R, -C(O)OR, -C(O) _NR2 , -C(O)NROR, _-CR2NRC (O)R, _-CR2NRC (O) _NR2 , -OC(O)R, -OC(O) _NR2 , -OP(O) _R2 , -OP(O)(OR) ₂ , -OP(O)(OR) _NR2 , -OP( _O )( _NR2 )2-, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) _2R , -NP(O) _R2 , -NRP(O)(OR) ₂ , -NRP(O)(OR) _NR2 , -NRP(O)( _NR2 ) ₂ and -NRS(O) _2R , or two ^Rw groups attached to the same carbon atom are optionally taken together to form a spiro-fused ring selected from: 3-5 membered saturated or partially unsaturated carbocyclyl and 3-5 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is hydrogen. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is ^RA . In some embodiments, one or more of ^Rw , ^Rx , Ry ^, and ^Rz is halogen. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -CN. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -NO ₂ . In some embodiments, one or more of ^Rw , Rx, ^{Ry ,} and ^Rz is -OR. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -SR. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -NR ₂ . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -SiR ₃ . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -S(O) ₂ R. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -S(O) _2NR2 . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -S(O) _R . In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is -C(O)R. In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is -C(O)OR. In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is -C(O) _NR2 . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -C(O)NROR. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is _-CR2NRC (O)R. In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is _-CR2NRC (O) _NR2 . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -OC(O)R. In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -OC(O)NR ₂ . In some embodiments, one or more of Rw, ^{Rx , Ry,} and ^Rz is -OP(O)R ₂ . In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is -OP(O)(OR) ₂ . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -OP(O)(OR)NR ₂ . In some embodiments, one or more of ^Rw , ^Rx , ^Ry, and ^Rz is -OP(O)(NR ₂ ) ₂ -. In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is -NRC(O)OR. In some embodiments, one or more of ^Rw , ^Rx , ^Ry , and ^Rz is -NRC(O)R. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NRC (O) N (R) _2. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NRS (O) ₂ R. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NP (O) R _2. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NRP (O) (OR) _2. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NRP (O) (OR) NR _2. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NRP (O) (NR ₂ ) _2. In some embodiments, one or more of R ^w , R ^x , R ^y and R ^z is -NRS (O) ₂ R. In some embodiments, two R ^w groups attached to the same carbon atom together form a 3-5 membered saturated or partially unsaturated carbocyclic spiro fused ring. In some embodiments, two R ^w groups attached to the same carbon atom are optionally taken together to form a 3-5 membered saturated or partially unsaturated heterocyclic spiro fused ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^w is fluoro. In some embodiments, R ^w is chloro. In some embodiments, R ^w is bromo. In some embodiments, R ^w is methyl. In some embodiments, R ^w is isopropyl. In some embodiments, R ^w is -CHF ₂ . In some embodiments, R ^w is -CF ₃ . In some embodiments, R ^w is -CH ₂ CHF ₂ . In some embodiments, R ^w is -CH ₂ CF ₃ . In some embodiments, R ^w is -CH(Me)CF ₃ . In some embodiments, R ^w is -CONH ₂ . In some embodiments, R ^w is In some embodiments, R ^is In some embodiments, R ^is In some embodiments, two R ^w are cyclized to form a cyclopropylene.

In some embodiments, R ^x is bromine. In some embodiments, R ^x is -CF ₃ . In some embodiments, R ^x is -OC _1-6 cycloalkyl. In some embodiments, R ^x is -O-cyclohexyl.

In some embodiments, R ^y is methyl.

In some embodiments, R ^w , R ^x , R ^{y ,} and R ^z are selected from those depicted in Table 1 below.

As generally defined above, each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same nitrogen are optionally taken together with their intervening atoms to form, in addition to the nitrogen atom to which they are attached, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C _1-6 aliphatic group. In some embodiments, R is a C _1-6 alkyl group (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is a C _1-6 haloalkyl group (e.g., -CF ₃ , CHF ₂ , etc.). In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen together with their intervening atoms form, in addition to the nitrogen atom to which they are attached, a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

As generally defined above, ^Lx and ^Ly are independently a covalent bond or a _C1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S( _O )-, -S(O) _2- , or -CR=CR-.

In some embodiments, ^Lx is a covalent bond. In some embodiments, ^Lx is a _C1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-.

In some embodiments, ^Ly is a covalent bond. In some embodiments, ^Ly is a _C1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-.

In some embodiments, L ^x is -C(O)-. In some embodiments, L ^x is -S(O) ₂ -.

In some embodiments, ^Ly is -C(O)-.

In some embodiments, ^Lx and ^Ly are selected from those depicted in Table 1 below.

As generally defined above, v is 0 or 1.

In some embodiments, v is 0. In some embodiments, v is 1.

In some embodiments, v is selected from those depicted in Table 1 below.

As generally defined above, w, x, y and z are independently 0, 1, 2, 3 or 4.

In some embodiments, one or more of w, x, y, and z is 0. In some embodiments, one or more of w, x, y, and z is 1. In some embodiments, one or more of w, x, y, and z is 2. In some embodiments, one or more of w, x, y, and z is 3. In some embodiments, one or more of w, x, y, and z is 4.

In some embodiments, w, x, y, and z are selected from those depicted in Table 1 below.

In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, the CBM is

In some embodiments, CBM is In some embodiments, CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, the CBM is In some embodiments, CBM is In some embodiments, the CBM is In some embodiments, the CBM is

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-1:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² and R ³ is as defined and described in WO 2020/157652 and US 2020/247784, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-2:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , R ⁵ , Ring A, and n is as defined and described in WO 2020/168197 and US 2020/392139, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-3:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and ^described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , R ⁵ , R 6 , R ⁷ , R ⁸ , X and Y are as defined and described in WO 2020/205560 and US 2020/399273, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2/4/6 binding moiety, thereby forming a compound of formula I-e-4:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ^2A , R ^2B , R ³ , R ⁴ , p, q and r are as defined and described in WO 2018/033815 and US 10,233,188, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-5:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , R ⁴ and Ring A is as defined and described in WO 2020/206137, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-6:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , n and Ring A is as defined and described in WO 2020/180959 and US 2021/017156, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-7:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is as defined and described in WO 2020/168178 and US 2020/316064, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-8:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ³ , R ⁸ , R ⁸ ′, ^RA , X ¹ , Y, Z ¹ , Z ² , n, m and Ring A is as defined and described in WO 2020/223558 and US 2020/347066, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-9:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ³ , R ⁸ , X ¹ , X ² , X ³ , Y, Z ¹ , Z ² , n and Ring A is as defined and described in WO 2020/223469 and US 2020/347067, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein the CBM is a CDK2 binding moiety, thereby forming a compound of formula I-e-10:

or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ⁴ , R ⁵ , Ring A, Ring B, X, Y, Z, n and p is as defined and described in WO 2021/072232, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of Formula I, wherein the CBM is a CDK2 binding moiety selected from any one of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, and XXIV, or a pharmaceutically acceptable salt thereof, wherein L and DIM are as defined above and described in the Examples herein, and wherein each of the variables ^R1 , ^R3 , R11, ^R14 , ^R16 , ^R17 , ^R18 , ^R19 , ^R20 , ^R31 , ^R32 , ^{R32 *} , ^Rx , ^X1 , ^X2 , ^X3 , ^X4 , ^X5 , ^X6 , ^X7 , ^X8 , ^X9 , ^X10 , y, and y2 are as defined above and described in the Examples herein. 2020/206034, each of which is incorporated herein by reference in its entirety.

Ligase Binding Moiety (LBM)

In some embodiments, DIM is LBM. In some embodiments, LBM is an E3 ligase ligand known to those of ordinary skill in the art, including those described in: M. Toure, C.M. Kruss, Angewandte Chemie International Edition 2016, 55, 1966; T. Uehara et al. Nature Chemical Biology 2017, 13, 675; WO 2017/176708, US 2017/0281784, WO 2017/161119, WO 2017/176957, WO 2017/176958, WO 2015/160845, US 2015/0291562, WO 2016/197032, WO 2016/105518, US 2018/0009779, WO 2017/007612, 2018/0134684, WO 2013/106643, US 2014/0356322, WO 2002/020740, US 2002/0068063, WO 2012/078559, US 2014/0302523, WO2012/0032 81. US 2013/0190340, US 2016/0022642, WO 2014/063061, US 2015/0274738, WO2016/118666, US 2016/0214972, WO 2016/149668, US 2016/0272639, WO 2016/169989, US2018/0118733, WO 2016/197114, US 2018/0147202, WO 2017/011371, US 2017/0008904, WO2017/011590, US 2017/0037004, WO 2017/079 267. US 2017/0121321, WO 2017/117473, WO2017/117474, WO 2013/106646, WO 2014/108452, WO 2017/197036, US 2019/0076540, WO2017/197046, US 2019/0076542, WO 2017/197051, US 2019/0076539, WO 2017/197055, US 2019/0076541 and WO 2017/197056, the entire contents of each of which are incorporated herein by reference.

As defined herein and described below, where square brackets are used to delineate a formula, e.g. L is attached to a modifiable carbon, oxygen, nitrogen or sulfur atom within DIM or LBM, including substitution or replacement of groups defined in DIM or LBM.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is a celebron E3 ubiquitin ligase binding moiety, thereby forming a compound of Formula I-aa:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and wherein:

^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or

^X2 is a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from: -CR ₂ -, -NR-, -O-, -S- or -Si(R ₂ )-;

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ , or an optionally substituted C _1-4 aliphatic group;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N (R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC (O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)( NR ₂ ) ₂ or -N(R)S(O) ₂ R;

Ring A is a bicyclic or tricyclic ring selected from the following:

in

Ring B is a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

^R3 is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR;

Each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ is hydrogen, C _1-4 aliphatic or -CN;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

m is 0, 1, 2, 3 or 4;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

When the point of attachment of -( ^R2 ) _m is depicted with respect to ring B, it is contemplated and will be understood by one of ordinary skill in the art that the point of attachment of -( ^R2 ) _m can be on ring A and can also be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. When ^-R2 is attached to a nitrogen atom that is bound to ^R4 or ^R5 , ^R4 or ^R5 is not present and ^-R2 replaces an ^R4 or ^R5 group. When ^-R2 is attached to a carbon atom that is bound to ^R3 , ^R3 is not present and ^-R2 replaces an ^R3 group.

In some embodiments, the compound of formula I-aa above is provided as a compound of formula I-aa' or I-aa":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring A, L, L ¹ , R ¹ , R ² , X ¹ , X ² , X ³ and m is as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-cc:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the following: a covalent bond, _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic group;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

Ring A is a bicyclic or tricyclic ring selected from the following:

in

Ring B is a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

^R3 is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR;

Each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ is hydrogen, C _1-4 aliphatic or -CN;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 0, 1, 2, 3 or 4; and

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

When the point of attachment of -( ^R2 ) _m is depicted with respect to ring B, it is contemplated and will be understood by one of ordinary skill in the art that the point of attachment of -( ^R2 ) _m can be on ring A and can also be at any available carbon or nitrogen atom on ring A, including the ring to which ring B is fused. When ^-R2 is attached to a nitrogen atom that is bound to ^R4 or ^R5 , ^R4 or ^R5 is not present and ^-R2 replaces an ^R4 or ^R5 group. When ^-R2 is attached to a carbon atom that is bound to ^R3 , ^R3 is not present and ^-R2 replaces an ^R3 group.

In some embodiments, the compound of formula I-cc above is provided as a compound of formula I-cc' or formula I-cc":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring A, L, R ¹ , R ² , X ¹ and m are as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-dd:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or

^X2 is a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from: -CR ₂ -, -NR-, -O-, -S- or -Si(R ₂ )-;

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ or an optionally substituted C _1-4 aliphatic group;

Ring C is a monocyclic or bicyclic ring selected from the following:

Each of R ² and R ^3a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S( O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , - C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O )R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O) (NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)( NR ₂ ) ₂ or -N(R)S(O) ₂ R;

Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclic group, 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ is hydrogen, C _1-4 aliphatic or -CN;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

p is 0 or 1, wherein when p is 0, the bond connecting ring C and ring D is connected to and

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, the above formula I-dd compound is provided as a compound of formula I-dd' or formula I-dd":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring C, Ring D, L, L ¹ , R ¹ , R ² , R ^3a , X ¹ , X ² , X ³ , n, m and p are as defined above.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of formula I-ee:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the following: a covalent bond, _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic group;

Ring C is a monocyclic or bicyclic ring selected from the following:

each of R ² and R ^3a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R;

Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclic group, 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ is hydrogen, C _1-4 aliphatic or -CN;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1, wherein when p is 0, the bond connecting ring C and ring D is connected to and

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, the above compound of formula I-ee is provided as a compound of formula I-ee' or formula I-ee":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring C, Ring D, L, R ¹ , R ² , R ^3a , ^Xi , n, m and p are as defined above.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of formula I-ff:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or

^X2 is a carbon atom or a silicon atom;

X ³ is a divalent moiety selected from: -CR ₂ -, -NR-, -O-, -S- or -Si(R ₂ )-;

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)(R) ₂ , -Si(R) ₃ or an optionally substituted C _1-4 aliphatic group;

Ring C is a monocyclic or bicyclic ring selected from the following:

Each of R ² and R ^3a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S( O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , - C(O)N(R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O )R, -OC(O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O) (NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)( NR ₂ ) ₂ or -N(R)S(O) ₂ R;

Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclic group, 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R;

R ⁵ is hydrogen, C _1-4 aliphatic or -CN;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4;

p is 0 or 1; and

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, the above compound of formula I-ff is provided as a compound of formula I-ff' or formula I-ff":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring C, Ring D, L, L ¹ , R ¹ , R ² , R ^3a , X ¹ , X ² , X ³ , m, n and p are as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-gg:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the following: a covalent bond, _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic group;

Ring C is a monocyclic or bicyclic ring selected from the following:

each of R ² , R ^3a , and R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R;

Ring D is selected from 6-membered aryl, 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5- to 7-membered saturated or partially unsaturated carbocyclic group, 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

R ⁵ is hydrogen, C _1-4 aliphatic or -CN;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0 or 1; and

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, the above compound of formula I-gg is provided as a compound of formula I-gg' or formula I-gg":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring C, Ring D, L, R ¹ , R ² , R ^3a , ^Xi , m, n and p are as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-hh:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or

^X2 is a carbon atom, a nitrogen atom or a silicon atom;

X ³ is a divalent moiety selected from the group consisting of: a covalent bond, -CR ₂ -, -NR-, -O-, -S- or -SiR ₂ -;

R ¹ is absent, hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ or optionally substituted C _1-4 aliphatic;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N (R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP( O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -NP (O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -N(R)P(O)(NR ₂ ) ₂ or -N(R)S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each of Ring E, Ring F and Ring G is independently a condensed ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein Ring E, Ring F and Ring G are independently and optionally substituted with 1-2 oxo groups;

L ¹ is a covalent bond or a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-; and

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

When describing the ring E, ring F or ring G It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the ring where ring E or ring G is fused to ring F.

When the point of attachment of -( ^R2 ) _m is depicted with respect to Ring E, Ring F, or Ring G, it is contemplated and will be understood by one of ordinary skill in the art that the point of attachment of -( ^R2 ) _m can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom to which Ring E or Ring G and Ring F are fused.

When describing the ring E, ring F or ring G It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the carbon atom to which ring E or ring G and ring F are fused.

In some embodiments, the above compounds of formula I-hh are provided as compounds of formula I-hh' or formula I-hh":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, ring E, ring F, ring G, L, L ¹ , R ¹ , R ² , X ¹ , X ² , X ³ and m is as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-hh-1 or I-hh-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N (R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP( O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -NP (O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -N(R)P(O)(NR ₂ ) ₂ or -N(R)S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each of Ring E, Ring F and Ring G is independently a condensed ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein Ring E, Ring F and Ring G are independently and optionally substituted with 1-2 oxo groups;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16; and

R ⁴ , R ¹⁰ , R ¹¹ , R ¹⁵ , W ¹ , W ² and X are as defined in WO 2019/099868, the entire contents of each of which are incorporated herein by reference.

When describing ring E, ring F or ring G It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the ring where ring E or ring G is fused to ring F.

When the point of attachment of -( ^R2 ) _m is depicted with respect to Ring E, Ring F, or Ring G, it is contemplated and will be understood by one of ordinary skill in the art that the point of attachment of -( ^R2 ) _m can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom to which Ring E or Ring G and Ring F are fused.

When describing ring E, ring F or ring G It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the carbon atom to which ring E or ring G and ring F are fused.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-ii:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the following: a covalent bond, _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -Si(R) ₃ or an optionally substituted C _1-4 aliphatic group;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N (R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC (O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ or -N(R )S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each of Ring E, Ring F and Ring G is independently a condensed ring selected from the following: a 6-membered aryl group containing 0-3 nitrogen atoms, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein Ring E, Ring F and Ring G are independently and optionally substituted with 1-2 oxo groups; and

m is 0, 1, 2, 3 or 4.

When describing the ring E, ring F or ring G It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on ring E, ring F or ring G, including the ring where ring E or ring G is fused to ring F.

When the point of attachment of -( ^R2 ) _m is depicted with respect to Ring E, Ring F, or Ring G, it is contemplated and one of ordinary skill in the art will appreciate that the point of attachment of -( ^R2 ) _m can be at any available carbon or nitrogen atom on Ring E, Ring F, or Ring G, including the carbon atom to which Ring E or Ring G and Ring F are fused.

In some embodiments, the compound of formula I-ii above is provided in the form of a compound of formula I-ii' or formula I-ii":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, L, ring E, ring F, ring G, L, R ¹ , R ² , X ¹ and m is as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-jj:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or

^X2 is a carbon atom, a nitrogen atom or a silicon atom;

X ³ is a divalent moiety selected from the group consisting of: a covalent bond, -CR ₂ -, -NR-, -O-, -S- or -SiR ₂ -;

R ¹ is absent, hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ or optionally substituted C _1-4 aliphatic;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N (R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC (O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)( NR ₂ ) ₂ or -N(R)S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring E is a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring H is a fused ring selected from: a 7-9 membered saturated or partially unsaturated carbocyclyl or a heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, wherein Ring E is optionally further substituted with 1-2 oxo groups;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

m is 0, 1, 2, 3 or 4.

When describing about ring E or ring H It is expected and will be understood by those of ordinary skill in the art that The point of attachment of may be on any available carbon or nitrogen atom on ring E or ring H, including the carbon atom to which ring E and ring H are fused.

When the point of attachment of -( ^R2 ) _m is depicted with respect to Ring E and Ring H, it is contemplated and one of ordinary skill in the art will appreciate that the point of attachment of -( ^R2 ) _m can be on any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

When describing the ring E and ring H It is expected and will be understood by those of ordinary skill in the art that The point of attachment of may be on any available carbon or nitrogen atom on ring E or ring H, including the carbon atom to which ring E and ring H are fused.

In some embodiments, the above compound of formula I-jj is provided as a compound of formula I-jj' or formula I-jj":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring E, Ring H, L, L ¹ , R ¹ , R ² , X ¹ , X ² , X ³ and m is as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-kk:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the following: a covalent bond, _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -Si(R) ₃ or an optionally substituted C _1-4 aliphatic group;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N (R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC (O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ or -N(R )S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring E is a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring H is a ring selected from: a 7-9 membered saturated or partially unsaturated carbocyclyl or a heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, wherein Ring E is optionally further substituted with 1-2 oxo groups; and

m is 0, 1, 2, 3 or 4.

When describing about ring E or ring H It is expected and will be understood by those of ordinary skill in the art that The point of attachment of may be on any available carbon or nitrogen atom on ring E or ring H, including the carbon atom to which ring E and ring H are fused.

When the point of attachment of -( ^R2 ) _m is depicted with respect to Ring E and Ring H, it is contemplated and one of ordinary skill in the art will appreciate that the point of attachment of -( ^R2 ) _m can be on any available carbon or nitrogen atom on Ring E or Ring H, including the carbon atom to which Ring E and Ring H are fused.

When describing about ring E or ring H It is expected and will be understood by those of ordinary skill in the art that The point of attachment of may be on any available carbon or nitrogen atom on ring E or ring H, including the carbon atom to which ring E and ring H are fused.

In some embodiments, the above compound of formula I-kk is provided as a compound of formula I-kk' or formula I-kk":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring E, Ring H, L, R ¹ , R ² , X ¹ and m is as defined above.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming compounds of Formula I-11:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or

^X2 is a carbon atom, a nitrogen atom or a silicon atom;

X ³ is a divalent moiety selected from the group consisting of: a covalent bond, -CR ₂ -, -NR-, -O-, -S- or -SiR ₂ -;

R ¹ is absent, hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ or optionally substituted C _1-4 aliphatic;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N (R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC (O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)( NR ₂ ) ₂ or -N(R)S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each of Rings I and J is independently a fused ring selected from a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring K is a fused ring selected from: a 7-12 membered saturated or partially unsaturated carbocyclyl or a heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, wherein Ring H is optionally further substituted with 1-2 oxo groups;

L ¹ is a covalent bond or a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-; and

m is 0, 1, 2, 3 or 4.

When describing ring I, ring J and ring K It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on Ring I, Ring J or Ring K, including the carbon atom to which Ring I, Ring J and Ring K are fused.

When the point of attachment of -(R ² ) _m is depicted with respect to Ring I, Ring J, and Ring K, it is contemplated and will be understood by one of ordinary skill in the art that the point of attachment of -(R ² ) _m can be on any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atom to which Ring I, Ring J, and Ring K are fused.

When describing ring I, ring J and ring K It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on Ring I, Ring J or Ring K, including the carbon atom to which Ring I, Ring J and Ring K are fused.

In some embodiments, the above compound of formula I-11 is provided in the form of a compound of formula I-11' or formula I-11":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring I, Ring J, Ring K, L, L ¹ , R ¹ , R ² , X ¹ , X ² , X ³ and m is as defined above.

In certain embodiments, the present invention provides compounds of formula I-mm:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

^X1 is a divalent moiety selected from the following: a covalent bond, _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -Si(R) ₃ or an optionally substituted C _1-4 aliphatic group;

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, -S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N (R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC (O)N(R) ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ or -N(R )S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each of rings I and J is independently a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring K is a fused ring selected from: a 7-12 membered saturated or partially unsaturated carbocyclyl or a heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, wherein Ring H is optionally further substituted with 1-2 oxo groups; and

m is 0, 1, 2, 3 or 4.

When describing ring I, ring J and ring K It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on Ring I, Ring J or Ring K, including the carbon atom to which Ring I, Ring J and Ring K are fused.

When the point of attachment of -(R ² ) _m is depicted with respect to Ring I, Ring J, and Ring K, it is contemplated and will be understood by one of ordinary skill in the art that the point of attachment of -(R ² ) _m can be on any available carbon or nitrogen atom on Ring I, Ring J, or Ring K, including the carbon atom to which Ring I, Ring J, and Ring K are fused.

When describing ring I, ring J and ring K It is expected and will be understood by those of ordinary skill in the art that The point of attachment of can be on any available carbon or nitrogen atom on Ring I, Ring J or Ring K, including the carbon atom to which Ring I, Ring J and Ring K are fused.

In some embodiments, the above formula I-mm compound is provided as a compound of formula I-mm' or formula I-mm":

or a pharmaceutically acceptable salt thereof, wherein:

Each of CBM, Ring I, Ring J, Ring K, L, R ¹ , R ² , X ¹ and m is as defined above.

As described above, in another aspect, the present invention provides a compound of formula I-nn:

or a pharmaceutically acceptable salt thereof, wherein:

Ring M is selected from

Each of X ¹ , X ⁶ and X ⁷ is independently a divalent moiety selected from the group consisting of a covalent bond, -CH ₂ -, -CHCF ₃ -, -SO ₂ -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR ₂ -, -C(O)-, -C(S)- or

Each of X ³ and X ⁵ is independently a divalent moiety selected from: a covalent bond, -CR ₂ -, -NR-, -O-, -S- or -SiR ₂ -;

^X4 is a trivalent moiety selected from:

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Each R ^3a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N (R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP( O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -NP (O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -N(R)P(O)(NR ₂ ) ₂ or -N(R)S(O) ₂ R;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

each R ⁷ is independently hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH)R ₂ , -Si(OH) ₂ R, -SiR ₃ , or optionally substituted C _1-4 aliphatic; or

^R7 and ^X1 or ^X3 together with their intervening atoms form a 5-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

Two ^R7 groups on the same carbon optionally form, together with their intervening atoms, a 3-6 membered spiro-fused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

Two ^R groups on adjacent carbon atoms optionally form, together with their intervening atoms, a 3-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 7-13 membered saturated, partially unsaturated bridged heterocyclic ring, or a spiroheterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur;

Ring D is selected from a 6- to 10-membered aryl or heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

n is 0, 1, 2, 3 or 4; and

q is 0, 1, 2, 3 or 4.

As defined above and described herein, each of ^X1 , ^X6 and ^X7 is independently a divalent moiety selected from a covalent bond, _-CH2- , -C(R) _2- , -C(O)-, -C(S)-, -CH(R)-, -CH( _CF3 )-, -P(O)(OR)-, -P(O)(R)-, -P(O)( _NR2 )-, -S(O)-, -S(O) _2- , or

In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently a covalent bond. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -CH ₂ -. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -CR ₂ -. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -C(O)-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -C(S)-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -CH(R)-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -CH(CF ₃ )-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -P(O)(OR)-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -P(O)(R)-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -P(O)NR ₂ -. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -S(O)-. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -S(O) 2 -. In some embodiments, each of X ¹ , X ⁶ and X ⁷ is independently -P(O)NR ₂ -.

In some embodiments, each of X ¹ , X ⁶ , and X ⁷ is independently selected from those depicted in Table 1 below.

As defined above and described herein, X ² is a carbon atom, a nitrogen atom or a silicon atom.

In some embodiments, X ² is a carbon atom. In some embodiments, X ² is a nitrogen atom. In some embodiments, X ² is a silicon atom.

In some embodiments, ^X2 is selected from those depicted in Table 1 below.

As defined above and described herein, ^X3 is a divalent moiety selected from _-CH2- , _-CR2- , -NR-, _-CF2- , -CHF-, -S-, -CH(R)-, _-SiR2- , or -O-.

In some embodiments, each of ^X3 and ^X5 is independently _-CH2- . In some embodiments, each of ^X3 and ^X5 is independently -CR2-. In some embodiments, each of ^X3 and ^X5 is independently _-NR- . In some embodiments, each of ^X3 and ^X5 is independently -CF2-. In some embodiments, each of ^X3 and ^X5 is independently -CHF-. In some embodiments, each of ^X3 and ^X5 is independently -S-. In some embodiments, each of ^X3 and ^X5 is independently -CH(R ₎ -. In some embodiments, each of ^X3 and ^X5 is independently _-SiR2- . In some embodiments, each of ^X3 and ^X5 is independently -O-.

In some embodiments, each of ^X3 and ^X5 is independently selected from those depicted in Table 1 below.

As defined above and described herein, ^X4 is a trivalent moiety selected from:

In some embodiments, ^X4 is In some embodiments, ^X4 is In some embodiments, ^X4 is In some embodiments, ^X4 is In some embodiments, ^X4 is In some embodiments, ^X4 is In some embodiments, ^X4 is

In some embodiments, ^X4 is selected from those depicted in Table 1 below.

As defined above and described herein, R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ ^, -SiR ₃ , optionally substituted C _1-4 aliphatic, or R ¹ and Xi or X ⁴ together with their intervening atoms form a 5-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -OR. In some embodiments, R ^{1 is -SR. In some embodiments, R 1 is} -S(O)R. In some embodiments, R ¹ is -S(O) ₂ R. In some embodiments, R ¹ is -NR ₂ . In some embodiments, R ¹ is -P(O)(OR) ₂ . In some embodiments, R ¹ is -P(O)(NR ₂ )OR. In some embodiments, R ¹ is -P(O)(NR ₂ ) ₂ . In some embodiments, R ¹ is -Si(OH) ₂ R. In some embodiments, R ¹ is -Si(OH)R ₂ . In some embodiments, R ¹ is -SiR ₃ . In some embodiments, R ¹ is optionally substituted C _1-4 aliphatic. In some embodiments, R ¹ and X ¹ or X ⁴ together with their intervening atoms form a 5-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, R ¹ is selected from those depicted in Table 1 below.

As defined above and described herein, each R is independently hydrogen or an optionally substituted group selected from the group consisting of a _C1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, or two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C _1-6 aliphatic group. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur. In some embodiments, two R groups on the same nitrogen together with their intervening atoms form, in addition to the nitrogen, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

As defined above and described herein, each of ^R2 and ^R3a is independently hydrogen, ^-R6 , halogen, -CN, _-NO2 , -OR, -Si(OH) _2R , -Si(OH) _R2 , -SR, _-NR2 , _-SiR3 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, -C(O) _R , -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -C(R) _2N (R)C(O)R, -C(R) _2N (R)C(O) _NR2 , -OC(O)R, -OC(O) _NR2 , -OP(O) _R2 , -OP(O)(OR) ₂ , -OP(O)(OR) _NR2 , -OP(O)( _NR2 ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -N(R)P(O)(NR ₂ ) ₂ or -N(R)S(O) ₂ R .

In some embodiments, R ² and R ^3a are independently hydrogen. In some embodiments, R ² and R ^3a are independently -R ⁶ . In some embodiments, R ² and R ^3a are independently halogen. In some embodiments, R ² and R ^3a are independently -CN. In some embodiments, R ² and R 3a are independently -NO ₂ . In some embodiments, R ² and R ^3a are independently -OR. In some embodiments, R ² and R ^3a are independently -Si(OH) ₂ R. In some embodiments, R ² and R ^3a are independently -Si(OH)R ₂ . In some embodiments, R ² and R ^3a are independently -SR. In some embodiments, R ² and R ^3a are independently -NR ₂ . In some embodiments, R ² and R ^3a are independently -SiR ₃ . In some embodiments, R ² and R ^3a are independently -S ⁽ O) ₂ R. In some embodiments, R ² and R ^3a are independently -S(O) ₂ NR ₂ . In some embodiments, R ² and R ^3a are independently -S(O)R. In some embodiments, R ² and R ^3a are independently -C(O)R. In some embodiments, R ² and R ^3a are independently -C(O)OR. In some embodiments, R ² and R ^3a are independently -C(O)NR ₂ . In some embodiments, R ² and R ^3a are independently -C(O)N(R)OR. In some embodiments, R ² and R ^3a are independently -C(R) ₂ N(R)C(O)R. In some embodiments, R ² and R ^3a are independently -C(R) ₂ N(R)C(O)NR ₂ . In some embodiments, R ² and R ^3a are independently -OC(O)R. In some embodiments, R ² and R ^3a are independently -OC(O)NR ₂ . In some embodiments, R ² and R ^3a are independently -OP(O)R ₂ . In some embodiments, R ² and R ^3a are independently -OP(O)(OR) ₂ . In some embodiments, R ² and R ^3a are independently -OP(O)(OR)NR ₂ . In some embodiments, R ² and R ^3a are independently -OP(O)(NR ₂ ) ₂ -. In some embodiments, R ² and R ^3a are independently -N(R)C(O)OR. In some embodiments, R ² and R ^3a are independently -N(R)C(O)R. In some embodiments, R ² and R ^3a are independently -N(R)C(O)NR ₂ . In some embodiments, R ² and R ^3a are independently -NP(O)R ₂ . In some embodiments, R ² and R ^3a are independently -N(R)P(O)(OR) ₂ . In some embodiments, R ² and R ^3a are independently -N(R)P(O)(OR)NR ₂ . In some embodiments, R ² and R ^3a are independently -N(R)P(O)(NR ₂ ) ₂ . In some embodiments, R ² and R ^3a are independently -N(R)S(O) ₂ R.

In some embodiments, R ² and R ^3a are independently -OH. In some embodiments, R ² and R ^3a are independently -NH _2. In some embodiments, R ² and R ^3a are independently -CH ₂ NH _2. In some embodiments, R ² and R ^3a are independently -CH ₂ NHCOMe. In some embodiments, R ² and R ^3a are independently -CH ₂ NHCONHMe. In some embodiments, R ² and R ^3a are independently -NHCOMe. In some embodiments, R ² and R ^3a are independently -NHCONHEt. In some embodiments, R ² and R ^3a are independently -SiMe _3. In some embodiments, R ^{2 and R 3a are independently -SiMe 2 OH. In some embodiments, R 2 and R 3a} _are ^{independently -SiMe} (OH) _2. In some embodiments, R ² and R ^3a are independently In some embodiments, R ² and R ^3a are independently Br. In some embodiments, R ² and R ^3a are independently Cl. In some embodiments, R ² and R ^3a are independently F. In some embodiments, R ² and R ^3a are independently Me. In some embodiments, R ^{2 and R 3a are independently -NHMe. In some embodiments, R 2 and R 3a are independently} -NMe ₂ . In some embodiments, R ² and R ^3a are independently -NHCO ₂ Et. In some embodiments, R ² and R ^3a are independently -CN. In some embodiments, R ² and R ^3a are independently -CH ₂ Ph. In some embodiments, R ² and R ^3a are independently -NHCO ₂ tBu. In some embodiments, R ² and R ^3a are independently -CO ₂ tBu. In some embodiments, R ² and R ^3a are independently -OMe. In some embodiments, R ² and R ^3a are independently -CF ₃ .

In some embodiments, R ² or R ^3a is selected from those depicted in Table 1 below.

As defined above and described herein, ^R3 is hydrogen, halogen, -CN, _-NO2 , _-OR , _-NR2 , -SR, -S(O) _2R , -S(O) _2NR2 , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NR(OR), -OC(O)R, -OC( O)NR ₂ , -OP(O)(OR) ₂ , -OP(O)(NR ₂ ) ₂ , -OP(O)(OR)NR ₂ , -N(R)C(O)R, -N (R)C(O)OR, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -N(R)S(O) ₂ NR ₂ , -N(R )P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si (OH) ₂ R, -Si(OH)(R) ₂ or -Si(R) ₃ .

In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is halogen. In some embodiments, R ^{3 is -CN. In some embodiments, R 3 is} -NO ₂ . In some embodiments, R ^{3 is -OR. In some embodiments, R 3 is} -NR ₂ . In some embodiments, R ³ is -SR. In some embodiments, R ³ is -S(O) ₂ R. In some embodiments, R ³ is -S(O) ₂ NR ₂ . In some embodiments, R ³ is -S(O)R. In some embodiments, R ³ is -C(O)R. In some embodiments, R ³ is -C(O)OR. In some embodiments, R ³ is -C(O)NR ₂ . In some embodiments, R ³ is -C(O)NR(OR). In some embodiments, R ³ is -OC(O)R. In some embodiments, R ³ is -OC(O)NR ₂ . In some embodiments, R ³ is -OP(O)(OR) ₂ . In some embodiments, R ³ is -OP(O)(NR ₂ ) ₂ . In some embodiments, R ³ is -OP(O)(OR)NR ₂ . In some embodiments, R ³ is -N(R)C(O)R. In some embodiments, R ³ is -N(R)C(O)OR. In some embodiments, R ³ is -N(R)C(O)NR ₂ . In some embodiments, R ³ is -N(R)S(O) ₂ R. In some embodiments, R ³ is -N(R)S(O) ₂ NR ₂ . In some embodiments, R ³ is -N(R)P(O)(OR) ₂ . In some embodiments, R ^{3 is -N(R)P(O)(OR) 2 . In some embodiments, R 3} is -N(R)P(O)(OR)NR ₂ . In some embodiments, R ³ is -P(O)(OR) ₂ . In some embodiments, R ³ is -P(O)(NR ₂ )OR. In some embodiments, R ³ is -P(O)(NR ₂ ) ₂ . In some embodiments, R ³ is -Si(OH) ₂ R. In some embodiments, R ³ is -Si(OH)(R) ₂ . In some embodiments, R ³ is -Si(R) ₃ .

In some embodiments, R ³ is methyl. In some embodiments, R ³ is -OCH _3. In some embodiments, R ³ is chloro.

In some embodiments, R ³ is selected from those depicted in Table 1.

As defined above and described herein, each ^R4 is independently hydrogen, ^-R6 , halogen, -CN, _-NO2 , -OR, -SR, -NR2, -S(O) _2R , -S(O) _2NR2 , -S(O) _R , -C(O) _R , -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -P(O)(OR) ₂ , -P(O)( _NR2 )OR, or -P(O)( _NR2 ) ₂ .

In some embodiments, R ⁴ is hydrogen. In some embodiments, R ⁴ is -R ⁶ . In some embodiments, R ⁴ is halogen. In some embodiments, R ⁴ is -CN. In some embodiments, R ⁴ is -NO ₂ . In some embodiments, R ⁴ is -OR. In some embodiments, R ⁴ is -SR. In some embodiments, R ⁴ is -NR ₂ . In some embodiments, R ⁴ is -S(O) ₂ R. In some embodiments, R ⁴ is -S(O) ₂ NR ₂ . In some embodiments, R ⁴ is -S(O)R. In some embodiments, R ⁴ is -C(O)R. In some embodiments, R ⁴ is -C(O)OR. In some embodiments, R ⁴ is -C(O)NR ₂ . In some embodiments, R ⁴ is -C(O)N(R)OR. In some embodiments, R ⁴ is -OC(O)R. In some embodiments, R ⁴ is -OC(O)NR ₂ . In some embodiments, R ⁴ is -N(R)C(O)OR. In some embodiments, R ⁴ is -N(R)C(O)R. In some embodiments, R ⁴ is -N(R)C(O)NR ₂ . In some embodiments, R ⁴ is -N(R)S(O) ₂ R. In some embodiments, R ⁴ is -P(O)(OR) ₂ . In some embodiments, R ⁴ is -P(O)(NR ₂ )OR. In some embodiments, R ⁴ is -P(O)(NR ₂ ) ₂ .

In some embodiments, ^R4 is methyl. In some embodiments, ^R4 is ethyl. In some embodiments, ^R4 is cyclopropyl.

In some embodiments, R ⁴ is selected from those depicted in Table 1.

As defined above and described herein, R ⁵ is hydrogen, optionally substituted C _1-4 aliphatic, or -CN.

In some embodiments, R ⁵ is hydrogen. In some embodiments, R ⁵ is optionally substituted C _1-4 aliphatic. In some embodiments, R ⁵ is -CN.

In some embodiments, R ⁵ is selected from those depicted in Table 1.

As defined above and described herein, each R ^is independently an optionally substituted group selected from the group consisting of a _C1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur.

In some embodiments, ^R is an optionally substituted C _1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, ^R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur. In some embodiments, ^R is an optionally substituted ^5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, and sulfur.

In some embodiments, R ⁶ is selected from those depicted in Table 1.

As generally defined above, each R ⁷ is independently hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -N(R) ₂ , -P(O)(R) ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH)R ₂ , -Si(OH) ₂ R, -SiR ₃ , or optionally substituted C _1-4 aliphatic, or R ¹ and X ¹ or X ³ together with their intervening atoms form a 5-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or two R 1 on the same carbon are independently selected from boron, nitrogen, oxygen, silicon or sulfur. The ^R7 group is optionally taken together with its intervening atoms to form a 3-6 membered spiro fused ring or a 4-7 membered heterocycle with 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or two ^R7 groups on adjacent carbon atoms are optionally taken together with their intervening atoms to form a 3-7 membered saturated, partially unsaturated carbocycle or a heterocycle with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 7-13 membered saturated, partially unsaturated bridged heterocycle, or a spiro heterocycle with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur.

In some embodiments, R ⁷ is hydrogen. In some embodiments, R ⁷ is halogen. In some embodiments, R ⁷ is -CN. In some embodiments, R ⁷ is -OR. In some embodiments, R ^{7 is -SR. In some embodiments, R 7 is} -S(O)R. In some embodiments, R ⁷ is -S(O) ₂ R. In some embodiments, R ⁷ is -NR ₂ . In some embodiments, R ⁷ is -Si(R) ₃ . In some embodiments, R ⁷ is -P(O)(R) ₂ . In some embodiments, R ⁷ is -P(O)(OR) ₂ . In some embodiments, R ⁷ is -P(O)(NR ₂ )OR. In some embodiments, R ⁷ is -P(O)(NR ₂ ) ₂ . In some embodiments, R ⁷ is -Si(OH)R ₂ . In some embodiments, R ⁷ is -Si(OH) ₂ R. In some embodiments, R ⁷ is optionally substituted C _1-4 aliphatic. In some embodiments, R ⁷ and X ¹ or X ³ form 5-7 yuan saturation, partially unsaturated carbocyclic rings or heterocyclic rings with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur with their inserted atoms. In some embodiments, two R ⁷ groups on the same carbon are optionally formed with their inserted atoms 3-6 yuan spiral condensed rings or 4-7 yuan heterocyclic rings with 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. In some embodiments, two R ⁷ groups on adjacent carbon atoms are optionally formed with their inserted atoms 3-7 yuan saturation, partially unsaturated carbocyclic rings or heterocyclic rings with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur with their inserted atoms. In some embodiments, two R ⁷ groups on adjacent carbon atoms are optionally formed with their inserted atoms 7-13 yuan saturation, partially unsaturated bridged heterocyclic rings or heterocyclic rings with 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur.

In some embodiments, ^R is selected from hydrogen, halogen, -CN, -OR, _-NR or C _1-4 alkyl. In some embodiments, ^R is selected from hydrogen, halogen, -CN or C _1-4 alkyl. In some embodiments, ^R is fluorine. In some embodiments, two ^R groups on the same carbon optionally form a 3 or 4-membered spiro fused ring with their intervening atoms.

In some embodiments, R ⁷ is selected from those depicted in Table 1 below.

As defined above and described herein, Ring A is a bicyclic or tricyclic ring selected from:

In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is

In some embodiments, Ring A is selected from those depicted in Table 1 below.

As defined above and described herein, Ring B is a fused ring selected from the group consisting of a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl group, a 5- to 7-membered saturated or partially unsaturated heterocyclyl group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur;

In some embodiments, ring B is a fused 6-membered aryl. In some embodiments, ring B is a fused 6-membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, ring B is a fused 5 to 7-membered saturated or partially unsaturated carbocyclic group. In some embodiments, ring B is a fused 5 to 7-membered saturated or partially saturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. In some embodiments, ring B is a fused 5-membered heteroaryl having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur.

In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is

In some embodiments, Ring B is selected from those depicted in Table 1 below.

As defined above and described herein, Ring C is a monocyclic or bicyclic ring selected from:

In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is

In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is In some embodiments, Ring C is

In some embodiments, Ring C is a monocyclic or bicyclic ring selected from:

In some embodiments, Ring C is selected from those depicted in Table 1 below.

As defined above and described herein, Ring D is a ring selected from the following: a 6- to 10-membered aryl or heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, ring D is a 6- to 10-membered aryl group. In some embodiments, ring D is a 6- to 10-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring D is a 5- to 7-membered saturated or partially unsaturated carbocyclic group. In some embodiments, ring D is a 5- to 7-membered saturated or partially saturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur. In some embodiments, ring D is a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur.

In some embodiments, ring D is phenyl. In some embodiments, ring D is pyridyl. In some embodiments, ring D is isoquinoline. In some embodiments, ring D is imidazo[1,2-a]pyridine.

In some embodiments, Ring D is selected from those depicted in Table 1 below.

As defined above and described herein, each of Ring E, Ring F and Ring G is independently a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, wherein Ring E, Ring F and Ring G are independently and optionally substituted with 1-2 oxo groups.

In some embodiments, each of Ring E, Ring F and Ring G is independently a condensed ring selected from a 6-membered aryl group. In some embodiments, each of Ring E, Ring F and Ring G is independently a condensed ring selected from a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, each of Ring E, Ring F and Ring G is independently a condensed ring selected from a 5-7-membered saturated or partially unsaturated carbocyclic group. In some embodiments, each of Ring E, Ring F and Ring G is independently a condensed ring selected from a 5-7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. In some embodiments, each of Ring E, Ring F and Ring G is independently a condensed ring of a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, Ring E, Ring F and Ring G are independently and optionally substituted with 1-2 oxo groups.

In some embodiments, Ring F is

In some embodiments, each of Ring E and Ring G is independently In some embodiments, each of Ring E and Ring G is independently In some embodiments, each of Ring E and Ring G is independently In some embodiments, each of Ring E and Ring G is independently In some embodiments, each of Ring E and Ring G is independently

In some embodiments, Ring E, Ring F and Ring G are In some embodiments, Ring E, Ring F and Ring G are In some embodiments, Ring E, Ring F and Ring G are

In some embodiments, Ring E, Ring F, and Ring G are selected from those depicted in Table 1 below.

As defined above and described herein, Ring H is a ring selected from a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, wherein Ring E is optionally further substituted with 1-2 oxo groups.

In some embodiments, Ring H is a ring selected from: a 7-9 membered saturated or partially unsaturated carbocyclyl or heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon, or sulfur, wherein Ring H is optionally further substituted with 1-2 oxo groups.

As defined above and described herein, each of Ring I and Ring J is independently a fused ring selected from a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl group, a 5- to 7-membered saturated or partially unsaturated heterocyclyl group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, each of Ring I and Ring J is independently a 6-membered aryl group. In some embodiments, each of Ring I and Ring J is independently a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, each of Ring I and Ring J is independently a 5-7-membered saturated or partially unsaturated carbocyclic group. In some embodiments, each of Ring I and Ring J is independently a 5-7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. In some embodiments, each of Ring I and Ring J is independently a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring I and Ring J are selected from those depicted in Table 1 below.

As defined above and described herein, Ring K is a fused ring selected from a 7-12 membered saturated or partially unsaturated carbocyclyl or a heterocyclyl having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, wherein Ring H is optionally further substituted with 1-2 oxo groups.

In some embodiments, ring K is a fused ring selected from a 7-12 membered saturated or partially unsaturated carbocyclic group. In some embodiments, ring K is a 7-12 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur. In some embodiments, ring K is optionally further substituted with 1-2 oxo groups.

In some embodiments, Ring K is selected from those depicted in Table 1 below.

As defined above and described herein, ring M is selected from

In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is In some embodiments, ring M is

In some embodiments, Ring M is selected from those depicted in Table 1 below.

As defined above and described herein, L ¹ is a covalent bond or a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ -, or -(C)=CH-;

In some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is a C _1-3 aliphatic group. In some embodiments, L ¹ is -CH ₂ -. In some embodiments, L ¹ is -C(D)(H)-. In some embodiments, L ¹ is -C(D) ₂ -. In some embodiments, L ¹ is -CH ₂ CH ₂ -. In some embodiments, L ¹ is -NR-. In some embodiments, L ¹ is -CH ₂ NR-. In some embodiments, L ¹ is -O-. In some embodiments, L ¹ is -CH ₂ O-. In some embodiments, L ¹ is -S-. In some embodiments, L ¹ is -OC(O)-. In some embodiments, L ¹ is -C(O)O-. In some embodiments, L ¹ is -C(O)-. In some embodiments, L ¹ is -S(O)-. In some embodiments, L ¹ is -S(O) ₂ -. In some embodiments, L ¹ is -NRS(O) ₂ -. In some embodiments, L ¹ is -S(O) ₂ NR-. In some embodiments, L ¹ is -NRC(O)-. In some embodiments, L ¹ is -C(O)NR-.

In some embodiments, Ring L ¹ is selected from those depicted in Table 1 below.

As defined above and described herein, A single bond or a double bond.

In some embodiments, is a single bond. In some embodiments, It is a double bond.

In some embodiments, Select from those depicted in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16.

In some embodiments, m is selected from those depicted in Table 1 below.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In some embodiments, n is selected from those depicted in Table 1 below.

As defined above and described herein, p is 0 or 1.

In some embodiments, p is 0. In some embodiments, p is 1.

In some embodiments, p is selected from those depicted in Table 1 below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

In some embodiments, q is selected from those depicted in Table 1 below.

In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is

In some embodiments, the LBM is selected from those in Table 1 below.

In some embodiments, the present invention provides a compound of formula Ia, wherein LBM is according to formula I-aa To provide a compound of formula Ia-1:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , ^X3 , Ra, ^Rb , ^R1 , ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , L, ^L1 , ^Lx , Ring A, Ring ^W , Ring X, Ring Y, Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ia-1, wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, ring W is a cyclopentyl group, and ring X is a pyrazolyl group as shown, to provide compounds of formula Ia-2:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^Ra , ^Rb , R1, ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , L, ^Lx , Ring A, Ring ^Y , Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ia, wherein LBM is according to formula I-nn To provide a compound of formula Ia-3:

or a pharmaceutically acceptable salt thereof, wherein each of Ra, ^Rb , ^R3a , ^R7 , ^Rw , ^Rx , ^Ry , ^Rz , ^L , ^L1 , ^Lx , ring D, ring M, ring W, ring X, ring Y, ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ia-3, wherein ring M is ^L1 is a covalent bond, ring W is cyclopentyl, and ring X is pyrazolyl as shown to provide a compound of formula Ia-4:

or a pharmaceutically acceptable salt thereof, wherein each of ^Ra , ^Rb , ^R3a , R7, ^Rw , ^Rx , ^Ry , ^Rz , L, ^Lx , ring D, ring Y, ring Z, n, q, v, w, x, y and ^z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ib, wherein LBM is according to formula I-aa To provide a compound of formula Ib-1:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , ^X3 , R1, ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , ^L , ^L1 , ^Lx , Ring A, Ring W, Ring X, Ring Y, Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ib-1, wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, and ring X is a pyrimidinyl group as shown, to provide compounds of formula Ib-2:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^Ra , ^Rb , R1, ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , L, ^Lx , Ring A, Ring ^Y , Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ib-1, wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, ring W is 2-pyridone, and ring X is pyrimidinyl as shown, to provide compounds of formula Ib-3:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^Ra , ^Rb , R1, ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , L, ^Lx , Ring A, Ring ^Y , Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ib-1, wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, ring W is 2-pyrrolidinone, and ring X is pyrimidinyl as shown, to provide compounds of formula Ib-4:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^Ra , ^Rb , R1, ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , L, ^Lx , Ring A, Ring ^Y , Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ib, wherein LBM is according to formula I-nn To provide a compound of formula Ib-5:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ¹ , L ^x , ring D, ring M, ring W, ring X, ring Y, ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ib-5, wherein ring M is ^L1 is a covalent bond, and ring X is a pyrimidinyl group as shown to provide a compound of formula Ib-6:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ^x , ring D, ring W, ring Y, ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ib-5, wherein ring M is ^L1 is a covalent bond, ring W is 2-pyridone, and ring X is pyrimidinyl as shown to provide a compound of formula Ib-7:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring D, Ring Y, Ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ib-5, wherein ring M is ^L1 is a covalent bond, ring W is 2-pyrrolidinone, and ring X is pyrimidinyl as shown to provide a compound of formula Ib-8:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring D, Ring Y, Ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ic, wherein LBM is according to formula I-aa To provide a compound of formula Ic-1:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , ^X3 , R1, ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , ^L , ^L1 , ^Lx , Ring A, Ring W, Ring X, Ring Y, Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ic-1, wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, ring W is phenyl, and ring X is a pyrimidinyl group as shown, to provide compounds of formula Ic-2:

or a pharmaceutically acceptable salt thereof, wherein each of X1, ^R1 , ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , ^L , ^Lx , Ring A, Ring Y, Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ic, wherein LBM is according to formula I-nn To provide a compound of formula Ic-3:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ¹ , L ^x , ring D, ring M, ring W, ring X, ring Y, ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ic-3, wherein ring M is ^L1 is a covalent bond, ring W is phenyl, and ring X is pyrimidinyl as shown to provide a compound of formula Ic-4:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ^x , Ring D, Ring Y, Ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ie, wherein LBM is according to formula I-aa To provide a compound of formula Ie-1:

or a pharmaceutically acceptable salt thereof, wherein each of ^X1 , ^X2 , X3, ^R1 , ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , ^L , ^L1 , ^Lx , ^Ly , Ring A, Ring W, Ring X, Ring Y, Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ie-1, wherein X ² is a carbon atom, X ³ is -CH ₂ -, L ¹ is a covalent bond, and ring X is a pyrimidinyl group as shown, to provide compounds of formula Ie-2:

or a pharmaceutically acceptable salt thereof, wherein each of X1, ^R1 , ^R2 , ^Rw , ^Rx , ^Ry , ^Rz , ^L , ^Lx , ^Ly , Ring A, Ring Y, Ring Z, m, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula Ie, wherein LBM is according to formula I-nn To provide a compound of formula Ie-3:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ¹ , L ^x , ^Ly , ring D, ring M, ring W, ring X, ring Y, ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides compounds of formula Ie-3, wherein ring M is ^L1 is a covalent bond, and ring X is a pyrimidinyl group as shown to provide a compound of formula Ie-4:

or a pharmaceutically acceptable salt thereof, wherein each of R ^3a , R ⁷ , R ^w , R ^x , R ^y , R ^z , L, L ^x , ^Ly , ring D, ring W, ring Y, ring Z, n, q, v, w, x, y and z is as defined above and described in the Examples herein, alone and in combination.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9 or I-oo-10, respectively:

Or form the formulas I-oo'-1, I-oo'-2, I-oo'-3, I-oo'-4, I-oo'-5, I-oo'-6, I-oo' respectively -7, I-oo'-8, I-oo'-9 or I-oo'-10 compounds:

Or form the formulas I-oo”-1, I-oo”-2, I-oo”-3, I-oo”-4, I-oo”-5, I-oo”-6, I-oo” respectively. -7, I-oo”-8, I-oo”-9 or I-oo”-10 compounds:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein the variable Each of X, X ₁ , X ₂ , Y, R ₁ , R ₃ , R ₃ ′, R ₄ , R ₅ , t, m, and n is as defined and described in WO 2017/007612 and US 2018/0134684, the entire contents of each of which are incorporated herein by reference.

Therefore, in some embodiments, the present invention provides a compound of formula I-oo-1, I-oo-2, I-oo-3, I-oo-4, I-oo-5, I-oo-6, I-oo-7, I-oo-8, I-oo-9, I-oo-10, I-oo'-1, I-oo'-2, I-oo'-3, I-oo'-4, I-oo'-5, I-oo'-6, I-oo'-7, I-oo'-8, I-oo'-9, I-oo'-10, I-oo"-1, I-oo"-2, I-oo"-3, I-oo"-4, I-oo"-5, I-oo"-6, I-oo"-7, I-oo"-8, I-oo"-9 or I-oo"-10, or a pharmaceutically acceptable salt thereof, wherein:

Y is a bond, Y ₁ , O, NH, NR ₂ , C(O)O, OC(O), C(O)NR ₂ ′, NR ₂ ′C(O), Y ₁ -O, Y ₁ -NH, Y ₁ -NR ₂ , Y ₁ -C(O), Y ₁ -C(O)O, Y ₁ -OC(O), Y ₁ -C(O)NR ₂ ′, or Y ₁ -NR ₂ ′C(O), wherein Y ₁ is C ₁ -C ₆ alkylene, C ₂ -C ₆ alkenylene, or C ₂ -C ₆ alkynylene;

X is C(O) or C(R ₃ ) ₂ ;

X ₁ -X ₂ is C(R ₃ )═N or C(R ₃ ) ₂ -C(R ₃ ) ₂ ;

Each R ₁ is independently halogen, nitro, NH ₂ , OH, C(O)OH, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy;

R ₂ is C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, 3 to 8 membered heterocycloalkyl, C (O) -C ₁ -C ₆ alkyl, C (O) -C ₂ -C ₆ alkenyl, C (O) -C ₃ -C ₈ cycloalkyl or C (O) -3 to 8 membered heterocycloalkyl, and R ₂ is optionally substituted with one or more of halogen, N (R _a ) ₂ , NHC (O) R _a , NHC (O) OR _a , OR _b , C ₃ -C ₈ cycloalkyl, 3 to 8 membered heterocycloalkyl, C 6 -C ₁₀ aryl or 5 to 10 membered heteroaryl, wherein each of C 3 -C 8 cycloalkyl, 3 to 8 membered heterocycloalkyl, C ₆ -C 10 aryl or 5 to 10 membered heteroaryl is optionally further substituted with one or more of halogen, N (R a ) 2 , NHC (O) R a , NHC _{(O) OR} a , OR b , C ₃ -C ₈ cycloalkyl, 3 to 8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl , CN, nitro, OH, C(O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy or C ₁ -C ₆ haloalkoxy;

R ₂ ′ is H, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₈ cycloalkyl, or 3 to 8 membered heterocycloalkyl, and R ₂ ′, when not H, is optionally substituted with one or more of halogen, N(R _a ) ₂ , NHC(O)R _a , NHC(O)OR _a , OR _b , C ₃ -C ₈ cycloalkyl, 3 to 8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5 to 10 membered heteroaryl, wherein each of C ₃ -C ₈ cycloalkyl, 3 to 8 membered heterocycloalkyl, C ₆ -C ₁₀ aryl, or 5 to 10 membered heteroaryl is optionally further substituted with one or more of halogen, NH ₂ , CN, nitro, OH, C(O)OH, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkoxy, or C ₁ -C ₆ haloalkoxy;

Each R ₃ is independently H or C ₁ -C ₃ alkyl optionally substituted with C ₆ -C ₁₀ aryl or 5- to 10-membered heteroaryl;

Each R ₃ ′ is independently C ₁ -C ₃ alkyl;

Each R ₄ is independently H or C ₁ -C ₃ alkyl; or two R ₄ together with the carbon atom to which they are attached form a C(O), C ₃ -C ₆ carbocyclic ring or a 4-membered, 5-membered or 6-membered heterocyclic ring containing 1 or 2 heteroatoms selected from N and O;

R ₅ is H, C ₁ -C ₃ alkyl, F or Cl;

Each _Ra is independently H or _C1 - _C6 alkyl;

R _b is H or tosyl;

t is 0 or 1;

m is 0, 1, 2 or 3; and

n is 0, 1 or 2.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming compounds of formula I-pp-1, I-pp-2, I-pp-3, I-pp-4, I-pp-5 or I-pp-6, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein the variables A, G, G', _Q1 , _Q2 , _Q3 , _Q4 , R, R', W, X, Y, Z, Each of and n is as defined and described in WO 2016/197114 and US 2018/0147202, the entire contents of each of which are incorporated herein by reference.

In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is

In some embodiments, the LBM is selected from those in Table 1 below.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming compounds of formula I-qq-1, I-qq-2 or I-qq-3, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and ^described herein, and wherein the variables R ¹ , R ² , R ⁴ , R ⁵ , R ¹⁰ , R 11 , R ¹⁴ , R ¹⁷ , W ¹ , W ² , X, Each of and n is as defined in WO 2017/197051, which is incorporated herein by reference in its entirety, and wherein is connected to R ¹ (the ring formed by combining R ¹ and R ² ) or R ¹⁷ at the point of attachment of R ¹² as defined in WO 2017/197051, such that Replace the R ¹² substituent.

In some embodiments, the present invention provides compounds of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming compounds of formula I-rr-1, I-rr-2, I-rr-3 or I-rr-4, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and wherein the variables R ¹ , R ⁴ , R 10 ^, R ¹¹ , R ¹⁴ , R ¹⁶ , W ¹ , W ² , X, and n are each as defined in WO 2018/237026, each of which is incorporated herein by reference in its entirety, and wherein is connected to R ¹ or R ¹⁶ at the point of attachment of R ¹² as defined in WO 2018/237026, such that Replace the R ¹² substituent.

In some embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming compounds of Formula I-ss-1 or I-ss-3, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described herein, and wherein each of the variables R ¹ , R ¹⁴ and R ¹⁶ are as defined in WO 2018/237026, the entire contents of each of which are incorporated herein by reference, and wherein is connected to R ¹ or R ¹⁶ at the point of attachment of R ¹² as defined in WO 2018/237026, such that Replace the R ¹² substituent.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of formula I-tt-1, I-tt-2, I-tt-3, I-tt-4, I-tt-5, I-tt-6, I-tt-7 or I-tt-8:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein the variables Ar, ^R1 , ^R2 , ^{R3 , R4, R5, R6, R7, R8 , A , L} , x, y and Each of which is as defined and described in WO 2017/161119, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-uu:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables A, B, C, W, X, Y and Z are as defined and described in US 5,721,246, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of Formula I-vv:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ₁ , R ₂ and n is as described and defined in WO 2019/043214, the entire contents of each of which are incorporated herein by reference.

In some embodiments, the LBM is an IAP E3 ubiquitin ligase binding portion described in Varfolomeev, E. et al., IAP Antagonists Induce Autoubiquitination of c-IAPs, NF-κB activation, and TNFα-Dependent Apoptosis, Cell, 2007, 131(4): 669-81, such as:

in Attachment to modifiable carbon, oxygen, nitrogen or sulfur atoms.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety,

This forms a compound of formula I-ww-1, I-ww-2, I-ww-3, I-ww-4 or I-ww-5, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ ', R ² ', R ³ ', X and X' is as defined and described in WO 2013/106643 and US 2014/0356322, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety, thereby forming compounds of formula I-xx-1, I-xx-2, I-xx-3, I-xx-4, I-xx-5 or I-xx-6, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ ', R ² ', R ³ ', R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R ₁₁ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₃ , R ₂₅ , E, G, M, X, X', Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ and o are as defined and described in WO 2016/149668 and US 2016/0272639, the entire contents of each of which are incorporated herein by reference.

As used herein, any LBM The surrounding brackets describe The moiety is covalently attached to the LBM at any available modifiable carbon, nitrogen, oxygen or sulfur atom. For clarity and by way of example, such available modifiable carbon, nitrogen, oxygen or sulfur atoms in the following LBM compound structures are depicted below, wherein each wavy bond is defined as described Connection points:

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is a VHL E3 ubiquitin ligase binding moiety, thereby forming compounds of Formula I-yy-1, I-yy-2 or I-yy-3, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ^p , R ₉ , R _{10 , R 11 ,} R _14a , R _14b , R ₁₅ , R ₁₆ , W ³ , W ⁴ , W ⁵ , ^Xi , X ² and o is as defined and described in WO 2016/118666 and US 2016/0214972, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN or VHL E3 ubiquitin ligase binding moiety, thereby forming a compound of formula I-zz-1, I-zz-2, I-zz-3, I-zz-4, I-zz-5, I-zz-6 or I-zz-7:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables A ¹ , A ² , A ³ , R ⁵ , G and Z are as defined and described in WO 2017/176958.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety, thereby forming a compound of formula I-zz'-1, I-zz"-1, I-zz'-2, I-zz'-2, I-zz'-3, I-zz"-3, I-zz'-4, I-zz"-4, I-zz'-7 or I-zz"-7, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables A ¹ , A ² , A ³ , R ⁵ , G and Z are as defined and described in WO 2017/176958, the entire contents of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding portion, thereby forming a compound of formula I-aaa-1, I-aaa-2, I-aaa-3, I-aaa-4, I-aaa-5, I-aaa-6, I-aaa-7, I-aaa-8, I-aaa-9, I-aaa-10, I-aaa-11, I-aaa-12, I-aaa-13, I-aaa-14, I-aaa-15, I-aaa-16, I-aaa-17 or I-aaa-18, respectively:

R ₁₀ , R 11 , R ₁₂ , R ₁₃ , R 14 , R 15 , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R _{1 '} , R _{2 ' , R 3' , R 4' , R 5' , R 6 ' , R 7 ' , R 8 ' , R 9 ' , R 10 '} Each of R _11′ , R _12′ , R _1″ , A, A′, A″, X, Y and Z is as defined and described in WO 2017/011371 and US 2017/0008904, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is an MDM2 (i.e., human double minute 2 or HDM2) E3 ligase binding moiety, thereby forming compounds of formula I-aaa-19, I-aaa-20 or I-aaa-21, respectively

or a pharmaceutically acceptable salt thereof, wherein each of the variables R ^12c , R ^12d , R ¹³ , R ¹⁷ , R ^18b , R ^18c , R ^18d , A ⁵ , A ⁶ , A ⁷ , Q ¹ and Ar are as defined and described in WO 2017/176957 and US 2019/127387.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is an IAP E3 ubiquitin ligase binding moiety, thereby forming compounds of Formula I-bbb-1, I-bbb-2, I-bbb-3, or I-bbb-4, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ is as defined and described in WO 2017/011590 and US 2017/0037004, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, a DCAF15 E3 ubiquitin ligase binding moiety, or a VHL E3 ubiquitin ligase binding moiety; thereby forming a compound of formula I-ccc-1, I-ccc-2, or I-ccc-3:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein:

Each of X ¹ , X ^2a and X ^3a is independently a divalent moiety selected from the group consisting of a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

Each of ^X4a and ^X5a is independently a divalent moiety selected from: _-CH2- , -C(O)-, -C(S)- or

R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic group;

each of R ² , R ^3b , and R ^4a is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , or -N(R)S(O) ₂ R;

R ^5a is hydrogen or a C _1-6 aliphatic group;

each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

Ring ^Aa is a condensed ring selected from the following: a 6-membered aryl group containing 0-2 nitrogen atoms; a 5- to 7-membered partially saturated carbocyclic group; a 5- to 7-membered partially saturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring ^Ba is selected from a 6-membered aryl group containing 0-2 nitrogen atoms or an 8-10-membered bicyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Ring ^Ca is selected from a 6-membered aryl group containing 0-2 nitrogen atoms or a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

m is 0, 1, 2, 3 or 4;

o is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3 or 4; and

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In certain embodiments, the present invention provides a compound of formula I-ccc-1, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of formula I-ccc'-1 or I-ccc"-1:

or a pharmaceutically acceptable salt thereof, wherein CBM, L, Ring A ^a , X ¹ , X ^2a , X ^3a , R ¹ , R ² and m are as defined above.

As defined above and described herein, each of X ¹ , X ^2a and X ^3a is independently a divalent moiety selected from: a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or

In some embodiments, X ¹ is a covalent bond, -CH ₂ -, -C(O)-, -C(S)-, or

In some embodiments, X ¹ is selected from those depicted in Table 1 below.

In some embodiments, ^X2a is a covalent bond, _-CH2- , -C(O)-, -C(S)-, or

In some embodiments, X ^2a is selected from those depicted in Table 1 below.

In some embodiments, X ^3a is a covalent bond, -CH ₂ -, -C(O)-, -C(S)-, or

In some embodiments, X ^3a is selected from those depicted in Table 1 below.

As defined above and described herein, each of ^X4 and ^X5 is independently a divalent moiety selected from: _-CH2- , -C(O)-, -C(S)-, or

In some embodiments, X ^4a is -CH ₂ -, -C(O)-, -C(S)-, or

In some embodiments, X ^4a is selected from those depicted in Table 1 below.

In some embodiments, ^X5a is _-CH2- , -C(O)-, -C(S)- or

In some embodiments, ^X5a is selected from those depicted in Table 1 below.

As defined above and described herein, R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or optionally substituted C _1-4 aliphatic.

In some embodiments, R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic.

In some embodiments, R ¹ is selected from those depicted in Table 1 below.

As defined above and described herein, each of ^R2 , ^R3b and ^R4a is independently hydrogen, ^-R6 , halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O) _R , -C(O)R, -C(O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , or -N(R)S(O) _2R .

In some embodiments, R ² is hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC (O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R.

In some embodiments, R ² is selected from those depicted in Table 1 below.

In some embodiments, R ^3b is hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC (O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R.

In some embodiments, R ^3b is methyl.

In some embodiments, R ^3b is selected from those depicted in Table 1 below.

In some embodiments, R ^4a is hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC (O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R.

In some embodiments, R ^4a is methyl.

In some embodiments, R ^4a is selected from those depicted in Table 1 below.

As defined above and described herein, R ^5a is hydrogen or C _1-6 aliphatic.

In some embodiments, R ^5a is tert-butyl.

In some embodiments, R ^5a is selected from those depicted in Table 1 below.

As defined above and described herein, each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^R is an optionally substituted C _1-6 aliphatic. In some embodiments, ^R is an optionally substituted phenyl. In some embodiments, ^R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted ^5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ⁶ is selected from those depicted in Table 1 below.

As defined above and described herein, Ring ^Aa is a fused ring selected from: a 6-membered aryl group containing 0-2 nitrogen atoms; a 5- to 7-membered partially saturated carbocyclyl group; a 5- to 7-membered partially saturated heterocyclyl group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, ring ^Aa is a fused 6-membered aryl group containing 0-2 nitrogen atoms. In some embodiments, ring ^Aa is a fused 5-7 membered partially saturated carbocyclic group. In some embodiments, ring ^Aa is a fused 5-7 membered partially saturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, ring ^Aa is a fused 5-7 membered partially saturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, Ring ^Aa is a fused phenyl.

In some embodiments, Ring ^Aa is selected from those depicted in Table 1 below.

As defined above and described herein, Ring ^Ba is selected from a 6-membered aryl group containing 0-2 nitrogen atoms or an 8-10 membered bicyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, ring ^Ba is a 6-membered aryl group containing 0-2 nitrogen atoms. In some embodiments, ring ^Ba is an 8-10 membered bicyclic heteroaryl group having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Ring ^Ba is

In some embodiments, Ring ^Ba is selected from those depicted in Table 1 below.

As defined above and described herein, Ring ^Ca is selected from a 6-membered aryl group containing 0-2 nitrogen atoms or a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, ring ^Ca is a 6-membered aryl group containing 0-2 nitrogen atoms. In some embodiments, ring ^Ca is a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, ring ^Ca is

In some embodiments, Ring ^Ca is selected from those depicted in Table 1 below.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

In some embodiments, m is selected from those depicted in Table 1 below.

In some embodiments, o is selected from those depicted in Table 1 below.

As defined above and described herein, o is 0, 1, 2, 3 or 4.

In some embodiments, o is 0. In some embodiments, o is 1. In some embodiments, o is 2. In some embodiments, o is 3. In some embodiments, o is 4.

In some embodiments, o is selected from those depicted in Table 1 below.

As defined above and described herein, q is 0, 1, 2, 3 or 4.

In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

In some embodiments, q is selected from those depicted in Table 1 below.

As defined above and described herein, each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form, in addition to the nitrogen, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is phenyl. In some embodiments, R is a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are optionally combined with their intervening atoms to form, in addition to the nitrogen, a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R is selected from those depicted in Table 1 below.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety, thereby forming a compound of formula I-ddd:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ₉ , R ₁₀ , R ₁₁ , R _14a and R ₁₅ are as described and defined in WO 2017/030814 , WO 2016/118666 , and US 2017/0327469 , the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety, thereby forming a compound of formula I-eee-1 or I-eee-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables X, W, R9, _R10 , _R11 , _R14a and _R14b , _R15 , ^R16 and o are as described and defined in WO 2017/030814, WO 2016/118666 and US 2017/0327469, the entire contents of each of which are _incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an IAP binding moiety, thereby forming a compound of formula I-fff:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables W, Y, Z, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as described and defined in WO 2014/044622, US 2015/0225449, WO 2015/071393 and US 2016/0272596, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an MDM2 binding moiety, thereby forming a compound of formula I-ggg:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, as described and defined in Hines, J. et al., Cancer Res. (Digital Object Identifier: 10.1158/0008-5472.CAN-18-2918), the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is a DCAF16 binding moiety, thereby forming a compound of Formula I-hhh:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, as described and defined in Zhang, X. et al., bioRxiv (Digital Object Identifier: https://doi.org/10.1101/443804), the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is the RNF114 binding moiety, thereby forming compounds of Formula I-iii:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, as described and defined in Spradin, J.N. et al., BioArchive (Digital Object Identifier: https://doi.org/10.1101/436998), the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an RNF4 binding moiety, thereby forming a compound of formula I-jjj:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, as described and defined in Ward, C.C. et al., BioArchive (Digital Object Identifier: https://doi.org/10.1101/439125), the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety, thereby forming a compound of formula I-nnn-1 or I-nnn-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ² , R ³ , X and Y are as defined and described in WO 2019/084026, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a VHL binding moiety, thereby forming a compound of formula I-ooo-1 or I-ooo-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ³ and Y is as defined and described in WO 2019/084030, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an E3 ubiquitin ligase (celebron) binding moiety, thereby forming a compound of formula I-ppp-1, I-ppp-2, I-ppp-3 or I-ppp-4:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and ^described herein, and wherein each of the variables R ⁴ , R ¹⁰ , R ¹¹ , R ¹⁵ , R 16 , R ¹⁷ , W ¹ , W ² and X are as defined in WO 2019/099868, which is incorporated herein by reference in its entirety, and wherein At the point of attachment of R ¹² is attached to R ¹⁷ or R ¹⁶ as defined in WO 2018/237026 such that Replace the R ¹² substituent.

In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is

In certain embodiments, the present invention provides compounds of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety, thereby forming a compound of formula I-qqq:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, wherein:

Each X ¹ is independently -CH ₂ -, -O-, -NR-, -CF ₂ -, -C(O)-, -C(S)- or

^X2 and ^X3 are independently _-CH2- , -C(O)-, -C(S)- or

^Z1 and ^Z2 are independently a carbon atom or a nitrogen atom;

Ring A is a fused ring selected from the following: benzo, a 4-6 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -S-, -C(O)-, -C(S)-, -CR ₂ -, -CRF-, -CF ₂ -, -NR- or -S(O) ₂ -;

Each R ¹ is independently selected from hydrogen, R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -CF ₂ R, -CR ₂ F, -CF ₃ , -CR ₂ (OR), -CR ₂ (NR ₂ ), -C(O)R, -C(O)OR, - C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -C(S)NR ₂ , -N(R)C(O) OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -OP(O)R ₂ , -OP(O) (OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ , -Si(OR)R ₂ and -SiR ₃ ; or

two R ¹ groups are optionally taken together to form an optionally substituted 5-8 membered partially unsaturated or aromatic fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

Each R is independently selected from hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form an optionally substituted 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the carbon or nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

R ² is selected from or hydrogen;

Ring B is phenyl, a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring, or a heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Ring B is further optionally substituted with 1-2 oxo groups;

Each R ³ is independently selected from hydrogen, R ⁴ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -CF ₂ R, -CF ₃ , -CR ₂ (OR), -CR ₂ (NR ₂ ), -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR) NR ₂ , -OP(O)(NR ₂ ) ₂ and -SiR ₃ ;

each R ⁴ is independently selected from an optionally substituted group selected from a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

is a single bond or a double bond;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4; and

o is 0, 1, or 2.

As defined above and described herein, each X ¹ is independently a covalent bond, -CH ₂ -, -O-, -NR-, -CF ₂ -, -C(O)-, -C(S)- or

In some embodiments, X ¹ is a covalent bond. In some embodiments, X ¹ is -CH ₂ -. In some embodiments, X ¹ is -O-. In some embodiments, X ¹ is -NR-. In some embodiments, X ¹ is -CF ₂ -. In some embodiments, ^{X 1} is In some embodiments, X ¹ is -C(O)-. In some embodiments, X ¹ is -C(S)-. In some embodiments, X ¹ is

In certain embodiments, X ¹ is selected from those shown in the compounds of Table 1.

As defined above and described herein, ^X2 and ^X3 are independently _-CH2- , -C(O)-, -C(S)- or

In some embodiments, ^X2 and ^X3 are independently _-CH2- . In some embodiments, ^X2 and ^X3 are independently -C(O)-. In some embodiments, ^X2 and ^X3 are independently -C(S)-. In some embodiments, ^X2 and ^X3 are independently

In certain embodiments, X ² and X ³ are independently selected from those groups shown in the compounds of Table 1.

As defined above and described herein, X ⁴ is a covalent bond, -CH ₂ -, -CR ₂ -, -O-, -NR-, -CF ₂ -, -C(O)-, -C(S)- or

As defined above and described herein, Z ¹ and Z ² are independently a carbon atom or a nitrogen atom.

In some embodiments, Z ¹ and Z ² are independently carbon atoms. In some embodiments, Z ¹ and Z ² are independently carbon atoms.

In certain embodiments, Z ¹ and Z ² are independently selected from those groups shown in the compounds of Table 1.

As defined above and described herein, Ring A is a fused ring selected from benzo or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, Ring A is benzo. In some embodiments, Ring A is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, Ring A is selected from those shown in the compounds of Table 1.

As defined above and described herein, L ¹ is a covalent bond or a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -S-, -C(O)-, -C(S)-, -CR ₂ -, -CRF-, -CF ₂ -, -NR-, or -S(O) ₂ -.

In some embodiments, L ¹ is a covalent bond. In some embodiments, L ¹ is a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -S-, -C(O)-, -C(S)-, -CR ₂ -, -CRF-, -CF ₂ -, -NR-, or -S(O) ₂ -.

In some embodiments, L ¹ is -C(O)-.

In certain embodiments, L ¹ is selected from those shown in the compounds of Table 1.

and ^R4 , -CN, _-NO2 , -OR, -SR, -NR2, -S(O) _2R , -S ₍ O) _2NR2 , -S(O)R, _-CF2R , -CF3, -CR2(OR), _{-CR2(NR2 )} , _-C (O) ^R , -C(O)OR, -C(O) _NR2 , -C( _O )N(R)OR, -OC(O ₎ R, -OC(O) _NR2 , -C(S) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -OP(O) _R2 , -OP(O)(OR) ₂ , -OP(O)(OR)NR2, - ₂ , -OP(O)(NR ₂ ) ₂ , -Si(OR)R ₂ and -SiR ₃ , or two R ¹ groups are optionally taken together to form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

In some embodiments, R ¹ is hydrogen. In some embodiments, R ¹ is R ⁴ . In some embodiments, R ¹ is halogen. In some embodiments, R ¹ is -CN. In some embodiments, R ¹ is -NO ₂ . In some embodiments, R ¹ is -OR. In some embodiments, R ¹ is -SR. In some embodiments, R ¹ is -NR ₂ . In some embodiments, R ¹ is -S(O) ₂ R. In some embodiments, R ¹ is -S(O) ₂ NR ₂ . In some embodiments, R ¹ is -S(O)R. In some embodiments, R ¹ is -CF ₂ R. In some embodiments, R ¹ is -CF ₃ . In some embodiments, R ¹ is -CR ₂ (OR). In some embodiments, R ¹ is -CR ₂ (NR ₂ ). In some embodiments, R ¹ is -C(O)R. In some embodiments, R ¹ is -C(O)OR. In some embodiments, R ¹ is -C(O)NR ₂ . In some embodiments, R ¹ is -C(O)N(R)OR. In some embodiments, R ¹ is -OC(O)R. In some embodiments, R ¹ is -OC(O)NR ₂ . In some embodiments, R ¹ is -C(S)NR ₂ . In some embodiments, R ¹ is -N(R)C(O)OR. In some embodiments, R ¹ is -N(R)C(O)R. In some embodiments, R ¹ is -N(R)C(O)NR ₂ . In some embodiments, R ¹ is -N(R)S(O) ₂ R. In some embodiments, R ¹ is -OP(O)R ₂ . In some embodiments, R ¹ is -OP(O)(OR) ₂ . In some embodiments, R ¹ is -OP(O)(OR) 2 . In some embodiments, R 1 is -OP(O)(OR)NR ₂ . In some embodiments, R ¹ is -OP(O)(NR ₂ ) ₂ . In some embodiments, R ¹ is -Si(OR)R ₂ . In some embodiments, R ¹ is -SiR ₃ . In some embodiments, two R ¹ groups are optionally taken together to form an optionally substituted 5-8 membered partially unsaturated or aryl fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, each R ¹ is independently selected from those shown in the compounds of Table 1.

As defined above and described herein, each R is independently selected from hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form, in addition to the carbon or nitrogen, an optionally substituted 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C _1-6 aliphatic group. In some embodiments, R is an optionally substituted phenyl group. In some embodiments, R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, two R groups on the same carbon or nitrogen are optionally taken together with their intervening atoms to form, in addition to the carbon or nitrogen, an optionally substituted 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

As defined above and described herein, R is selected ^from or hydrogen.

In some embodiments, ^R2 is In some embodiments, R ² is hydrogen.

In certain embodiments, R ² is selected from those shown in the compounds of Table 1.

As defined above and described herein, Ring B is phenyl, a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Ring B is further optionally substituted with 1-2 oxo groups.

In some embodiments, ring B is phenyl. In some embodiments, ring B is a 4-10 membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring B is a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ring B is further optionally substituted with 1-2 oxo groups.

In certain embodiments, Ring B is selected from those shown in the compounds of Table 1.

As defined above and described herein, each ^R3 is independently selected from hydrogen, ^R4 , halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _2NR2 , -S(O)R, _-CF2R , _-CF3 , _-CR2 (OR), _-CR2 ( _NR2 ), -C(O)R, _-C (O)OR, -C(O) _NR2 , -C(O)N(R)OR, -OC(O)R, -OC(O) _NR2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O) _NR2 , -N(R)S(O) _2R , -OP(O) _R2 , -OP(O)(OR) ₂ , -OP(O)(OR) _NR2 , -OP(O)(NR2), or ₂ ) ₂ and -SiR ₃ .

In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is R ⁴ . In some embodiments, R ³ is halogen. In some embodiments, R ³ is -CN. In some embodiments, R ³ is -NO ₂ . In some embodiments, R ³ is -OR. In some embodiments, R ³ is -SR. In some embodiments, R ³ is -NR ₂ . In some embodiments, R ³ is -S(O) ₂ R. In some embodiments, R ³ is -S(O) ₂ NR ₂ . In some embodiments, R ³ is -S(O)R. In some embodiments, R ³ is -CF ₂ R. In some embodiments, R ³ is -CF ₃ . In some embodiments, R ³ is -CR ₂ (OR). In some embodiments, R ³ is -CR ₂ (NR ₂ ). In some embodiments, R ³ is -C(O)R. In some embodiments, R ³ is -C(O)OR. In some embodiments, R ³ is -C(O)NR ₂ . In some embodiments, R ³ is -C(O)N(R)OR. In some embodiments, R ³ is -OC(O)R. In some embodiments, R ³ is -OC(O)NR ₂ . In some embodiments, R ³ is -N(R)C(O)OR. In some embodiments, R ³ is -N(R)C(O)R. In some embodiments, R ³ is -N(R)C(O)NR ₂ . In some embodiments, R ³ is -N(R)S(O) ₂ R. In some embodiments, R ³ is -OP(O)R ₂ . In some embodiments, R ³ is -OP(O)(OR) ₂ . In some embodiments, R ³ is -OP(O)(OR)NR ₂ . In some embodiments, R ³ is -OP(O)(NR ₂ ) ₂ . In some embodiments, R ³ is -SiR ₃ .

In certain embodiments, R ³ is selected from those shown in the compounds of Table 1.

As defined above and described herein, each R ⁴ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

In some embodiments, ^R is an optionally substituted C _1-6 aliphatic. In some embodiments, R is an optionally substituted phenyl. In some embodiments, ^R is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R is ^an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In certain embodiments, R ⁴ is selected from those shown in the compounds of Table 1.

As defined above and described herein, A single bond or a double bond.

In some embodiments, is a single bond. In some embodiments, It is a double bond.

In certain embodiments, Select from those shown in the compounds of Table 1.

As defined above and described herein, m is 0, 1, 2, 3 or 4.

In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

In certain embodiments, m is selected from those shown in the compounds of Table 1.

As defined above and described herein, n is 0, 1, 2, 3 or 4.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

In certain embodiments, n is selected from those shown in the compounds of Table 1.

As defined above and described herein, o is 0, 1 or 2.

In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 2.

In certain embodiments, o is selected from those shown in the compounds of Table 1.

In some embodiments, the present invention provides a compound of formula I-qqq, wherein ring A is benzo, o is 1, ^X1 is _-CH2- , ^X2 and ^X3 are -C(O)-, and ^Z1 and ^Z2 are carbon atoms as shown, to provide a compound of formula I-qqq-1:

or a pharmaceutically acceptable salt thereof, wherein each of CBM, L, L ¹ , R ¹ , R ² and m is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula I-qqq, wherein ring A is benzo, o is 1, X ¹ , X ² and X ³ are -C(O)-, and Z ¹ and Z ² are carbon atoms as shown, to provide a compound of formula I-qqq-12:

or a pharmaceutically acceptable salt thereof, wherein each of CBM, L, L ¹ , R ¹ , R ² and m is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is In some embodiments, LBM is

In some embodiments, the LBM is selected from those in Table 1 below.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is the RPN13 binding moiety, thereby forming a compound of Formula I-rrr:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables A, Y and Z are as described and defined in WO 2019/165229, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is an Ubr1 binding moiety as described in Shanmugasundaram, K. et al., J. Bio. Chem. 2019, Digital Object Identifier: 10.1074/jbc.AC119.010790, each of which is incorporated herein by reference in its entirety, thereby forming a compound of formula I-sss-1 or I-sss-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a CRBN E3 ubiquitin ligase binding moiety, thereby forming a compound of formula I-uuu-1, I-uuu-2, I-uuu-3 or I-uuu-4:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables Y, ^A1 and ^A3 is as described and defined in WO 2019/236483, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is human kelch-like ECH binding protein 1 (KEAP1), thereby forming a compound of formula I-vvv:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, alone and in combination.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a KEAP1 binding moiety as described in Lu et al., Euro. J. Med. Chem., 2018, 146: 251-9, thereby forming a compound of formula I-www:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, alone and in combination.

In certain embodiments, the present invention provides compounds of Formula I, wherein LBM is a KEAP1-NRF2 binding moiety, thereby forming compounds of Formula I-xxx or I-xxx-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R, R ₁ , R ₅ and R ₈ are as described and defined in WO 2020/018788, the entire contents of each of which are incorporated herein by reference.

In certain embodiments, the present invention provides a compound of formula I, wherein LBM is a KEAP1-NRF2 binding moiety as described in Tong et al., “Targeted Protein Degradation via a Covalent Reversible Degrader Based on Bardoxolone”, ChemRxiv 2020, thereby forming a compound of formula I-yyy-1 or I-yyy-2:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, alone and in combination.

In some embodiments, LBM is In some embodiments, LBM is

Degradation Inducing Fraction (DIM)

In certain embodiments, the present invention provides compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as described above and herein, and DIM is a degradation inducing moiety selected from LBM, a lysine mimetic, or a hydrogen atom.

In some embodiments, DIM is LBM as described above and herein. In some embodiments, DIM is a lysine mimetic. In some embodiments, the covalent attachment of ubiquitin to CDK2 protein is achieved via the action of a lysine mimetic. In some embodiments, after the compound of Formula I is bound to the CDK2 protein, the portion simulating lysine undergoes ubiquitination, thereby marking the CDK2 protein for degradation via the ubiquitin-proteasome pathway (UPP).

In some embodiments, DIM is In some embodiments, DIM is In some embodiments, DIM is

In some embodiments, the DIM is selected from those depicted in Table 2 below.

In some embodiments, the present invention provides a compound of Formula I that is a compound of Formula I-aaaa:

or a pharmaceutically acceptable salt thereof, wherein each of CBM and L is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of formula I that is a compound of formula I-aaaa-1:

or a pharmaceutically acceptable salt thereof, wherein each of CBM and L is as defined above and described in the Examples herein, alone and in combination.

In some embodiments, the present invention provides a compound of Formula I that is a compound of Formula I-aaaa-2:

or a pharmaceutically acceptable salt thereof, wherein each of CBM and L is as defined above and described in the Examples herein, alone and in combination.

In certain embodiments, the present invention provides compounds of formula I, wherein DIM is a lysine mimetic

This forms compounds of formula I-bbbb-1, I-bbbb-2 or I-bbbb-3, respectively:

or a pharmaceutically acceptable salt thereof, wherein L and CBM are as defined above and described in the Examples herein, and wherein each of the variables R ¹ , R ⁴ , R ⁵ , A, B, E, Y, Y′, Z, Z′, and k are as defined and described in U.S. Pat. No. 7,622,496 , each of which is incorporated herein by reference in its entirety.

Hydrogen Atom

In some embodiments, DIM is a hydrogen atom. In some embodiments, the covalent attachment of ubiquitin to the CDK2 protein is achieved via a provided compound wherein DIM is a hydrogen atom. In some embodiments, after the compound of Formula I is bound to the CDK2 protein, the hydrogen moiety completes ubiquitination, thereby marking the CDK2 protein for degradation via the ubiquitin-proteasome pathway (UPP).

In some embodiments, the DIM is selected from those depicted in Table 2 below.

In some embodiments, the present invention provides a compound of formula I, wherein DIM is a hydrogen atom, thereby forming a compound of formula I-cccc:

or a pharmaceutically acceptable salt thereof, wherein each of CBM and L is as defined above and described in the Examples herein, alone and in combination.

Linker (L)

As defined above and described herein, L is a divalent moiety that links the CBM to the LBM or the CBM to the DIM.

In some embodiments, L is a divalent moiety that connects the CBM to the LBM. In some embodiments, L is a divalent moiety that connects the CBM to the DIM. In some embodiments, L is a divalent moiety that connects the CBM to the lysine mimetic.

In some embodiments, L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C _1-50 hydrocarbon chain, wherein 0 to 6 methylene units of L are independently replaced by -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, in:

each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclylene, 4-11 membered saturated or partially unsaturated spirocarbocyclylene, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur,

Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or:

two R groups on the same nitrogen optionally form together with their intervening atoms a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and;

r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

In some embodiments, each -Cy- is independently an optionally substituted divalent phenylene. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic arylene. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated carbocyclylene. In some embodiments, each -Cy- is independently an optionally substituted 4-11 membered saturated or partially unsaturated spirocarbocyclylene. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene. In some embodiments, each -Cy- is independently an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 4-11 membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, each -Cy- is independently an optionally substituted 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is In some embodiments, -Cy- is

In some embodiments, -Cy- is optionally substituted with one or more fluorine atoms.

In some embodiments, -Cy- is selected from those depicted in Table 2 below.

In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 5. In some embodiments, r is 6. In some embodiments, r is 7. In some embodiments, r is 8. In some embodiments, r is 9. In some embodiments, r is 10.

In some embodiments, r is selected from those depicted in Table 2 below.

In some embodiments, L is -NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NR-(CH ₂ CH ₂ O) _{1- 10} CH ₂ CH ₂ -. In some embodiments, L is -Cy-NR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NR-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-NR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NR-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-NR-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NR-Cy-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-NR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NR-Cy-(C _1-10 aliphatic)-.

In some embodiments, L is -CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C 1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-CONR-(CH ₂ CH ₂ O) _{1- 10} CH ₂ CH ₂ -. In some embodiments, L is -Cy-CONR-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-CONR-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-CONR-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-CONR-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-CONR-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-CONR-Cy-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-CONR-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10 aliphatic )} -Cy-CONR-(C _1-10 aliphatic)-.

In some embodiments, L is -NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-NRCO-(CH ₂ CH ₂ O) _{1- 10} CH ₂ CH ₂ -. In some embodiments, L is -Cy-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NRCO-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NRCO-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-NRCO-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-NRCO-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-NRCO-. In some embodiments, L is -Cy-(C _{1-10 aliphatic)-Cy-NRCO-(C 1-10 aliphatic)-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-Cy-NRCO-(C 1-10 aliphatic )} -.

In some embodiments, L is -O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-O-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-O-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-O-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-O-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-O-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-O-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-Cy-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-O-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-O-Cy-(C _1-10 aliphatic)-.

In some embodiments, L is -Cy-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-. In some embodiments, L is -(C _1-10 aliphatic)-Cy-(CH ₂ CH ₂ O) _{1- 10} CH ₂ CH ₂ -. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-(C _1-10 aliphatic)-. In some embodiments, L is -Cy-(C _1-10 aliphatic)-Cy-(C _{1-10 aliphatic)-Cy-. In some embodiments, L is -Cy-(C 1-10 aliphatic)-Cy-(C 1-10 aliphatic )} -Cy-(C _1-10 aliphatic)-.

In some embodiments, L is -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NR-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-NR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NR-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-NR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -NR-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -NR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NR-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NR-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NR-Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -CONR-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -CONR-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) 1-10 -Cy-CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH 2 ) _1-10 -Cy-CONR-(CH 2 ) 1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -CONR-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-CONR-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -CONR-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-CONR-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -CONR-Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -NRCO-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NRCO-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -NRCO-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -NRCO-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _{1-10 -Cy-NRCO-. In some embodiments, L is -Cy-(CH 2 ) 1-10} -Cy-NRCO-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-NRCO-(CH ₂ ) _1-10 -. In some embodiments, _{L is -Cy-(CH 2 ) 1-10} -Cy-NRCO-(CH _{2 ) 1-10} -.

In some embodiments, L is -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -O-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-O-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -O-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-O-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -O-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -O-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-O-. In some embodiments, L is -Cy-(CH 2 ) _1-10 -O-Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-O-(CH _{2 ) 1-10} -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -O-Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is -Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ CH ₂ O) _1-10 CH ₂ CH ₂ -. In some embodiments, L is -Cy-(CH 2 ) _1-10 -Cy-. In some embodiments, L is -Cy-(CH ₂ ) 1-10 -Cy-(CH ₂ ) _1-10 -. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-(CH 2 ) 1-10 -Cy-. In some embodiments, L is -Cy-(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -Cy-. In some embodiments, L is -(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -Cy-(CH ₂ ) _1-10 -.

In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is

In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is In some embodiments, L is

In some embodiments, L is further selected from those depicted in Table B below.

In some embodiments, L is selected from those depicted in Table 1 below.

Without limitation, for example, when L is When L is connected to CBM and DIM, the connection point can be

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

In some embodiments, provided compounds or pharmaceutically acceptable salts thereof are selected from those wherein CBM is LBM is selected from any one of those in Table A below, and L is selected from any one of those in Table B below.

Table A. Exemplary E3 ligase binding moieties (LBMs)

Table B. Exemplary Linkers (L)

In some embodiments, the present invention provides compounds having a CBM described and disclosed herein, an LBM listed in Table A above, and a linker listed in Table B above, or a pharmaceutically acceptable salt thereof.

Exemplary compounds of the invention are listed in Table 1 below.

Table 1. Exemplary compounds

In some embodiments, the present invention provides compounds listed in Table 2 above or pharmaceutically acceptable salts thereof.

4. General Methods for Providing Compounds of the Invention

The compounds of the present invention can generally be prepared or isolated by synthetic and/or semi-synthetic methods known to those skilled in the art for similar compounds and by the methods described in detail in the Examples herein.

In the schemes below, when specific protecting groups, leaving groups or transformation conditions are depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups and transformation conditions are also suitable and contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M.B. Smith and J. March, 5th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R.C. Larock, 2nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, the entire contents of each of which are hereby incorporated herein by reference.

As used herein, the phrase "oxy protecting group" includes, for example, a carbonyl protecting group, a hydroxy protecting group, and the like. Hydroxyl protecting groups are well known in the art and include those described in detail in Organic Synthesis, T. W. Green and P. G. M. Woods, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. Examples of suitable hydroxy protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, aralkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formates, benzoyl formates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxo(oxo)valerates, 4,4-(ethylenedithio)valerates, pivalate (pivaloyl), crotonates, 4-methoxy-crotonates, benzoates, p-terephthalate, 2,4,6-trimethylbenzoate, carbonates (such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl ether, triethylsilyl ether, tert-butyldimethylsilyl ether, tert-butyldiphenylsilyl ether, triisopropylsilyl ether, and other trialkylsilyl ethers. Alkyl ethers include methyl ether, benzyl ether, p-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trityl ether, tert-butyl ether, allyl ether, and allyloxycarbonyl ether or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl ether, methylthiomethyl ether, (2-methoxyethoxy)methyl ether, benzyloxymethyl ether, β-(trimethylsilyl)ethoxymethyl ether, and tetrahydropyranyl ether. Examples of aralkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, as well as 2-pyridylmethyl and 4-pyridylmethyl.

Amino protecting groups are well known in the art and include those described in detail in Organic Synthesis, T. W. Green and P. G. M. Woods, 3rd edition, John Wiley & Sons, 1999, the entire contents of which are incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include tert-butoxycarbonyl (BOC), ethoxycarbonyl, methoxycarbonyl, trichloroethoxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

In the following schemes, when the provided compounds are formed with reactive moieties (e.g., amines, alcohols, etc.), it is not shown but it is generally understood and well known to those of ordinary skill in the art that the reactivity of such reactive moieties can be masked by employing suitable protecting groups which can thereafter be removed in situ or during additional synthetic steps.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 1 as described below:

Scheme 1: Synthesis of compounds of formula I

As depicted in Scheme 1 above, amine A-1 is coupled to acid A-2 using a coupling agent in the presence of a base such as DIPEA in a solvent such as DMF to form a compound of Formula I having a linker comprising an amide bond. The amide bond may be formed using coupling agents known in the art, such as, but not limited to, DCC, DIC, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 2 as described below:

Scheme 2: Synthesis of compounds of formula I

As depicted in Scheme 2 above, acid A-3 is coupled to amine A-4 using a coupling agent in the presence of a base such as DIPEA in a solvent such as DMF to form a compound of Formula I having a linker comprising an amide bond. and DIM and DIM, respectively. The amide bond may be formed using coupling agents known in the art such as, but not limited to, DCC, DIC, EDC, HATU, HBTU, HCTU, PyAOP, PyBOP, PyBrOP, BOP, BOP-Cl, DEPBT, T3P, TATU, TBTU, TNTU, TOTU, TPTU, TSTU, or TDBTU.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 3 as described below:

Scheme 3: Synthesis of compounds of formula I

As depicted in Scheme 3 above, SN _Ar displacement of fluoride A-6 by amine A-5 in the presence of a base such as DIPEA in a solvent such as DMF forms a compound of Formula I having a linker comprising a secondary amine. It represents the part of the linker between the CBM and the terminal amino group of A-5.

In certain embodiments, the compounds of the present invention are generally prepared according to Scheme 4 as described below:

Scheme 4: Synthesis of compounds of formula I

As depicted in Scheme 3 above, fluoride A-7 is subjected to S _N Ar displacement by amine A-8 in the presence of a base such as DIPEA in a solvent such as DMF to form a compound of Formula I having a linker comprising a secondary amine. It represents the part of the linker between DIM and the terminal amino group of A-8.

Scheme 5: Synthesis of compounds of formula I

As depicted in Scheme 7 above, reductive amination of a mixture of aldehyde A-9 and amine A-10 is carried out in the presence of a reducing agent such as NaHB(OAc) ₃ and a base such as KOAc in a solvent such as DMF/THF to form compounds of Formula I having a linker comprising a secondary amine. It represents the part of the linker between DIM and the terminal amino group of A-8.

Those skilled in the art will appreciate that the various functional groups present in the compounds of the invention, such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens, and nitriles, can be interconverted by techniques well known in the art including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. "March's Advanced Organic Chemistry", 5th edition, eds. Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing the compounds of the invention are described in the examples below.

5. Use, preparation and application

Pharmaceutically acceptable compositions

According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is such that it effectively degrades and/or inhibits the CDK protein or its mutant in a biological sample or patient in a measurable manner. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively degrades and/or inhibits the CDK protein or its mutant in a biological sample or patient in a measurable manner. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

The term "patient" as used herein means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

"Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an active metabolite or residue thereof.

As used herein, the term "inhibitory active metabolites or residues thereof" means metabolites or residues thereof that are also inhibitors of CDK proteins or mutants thereof.

As used herein, the term "depleted active metabolites or residues thereof" means metabolites or residues thereof that are also degraders of CDK protein or mutants thereof.

The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents can use water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are routinely used as solvents or suspension media.

For this purpose, any mild, fixed oil may be used, including synthetic mono- or di-glycerides. Fatty acids (such as oleic acid and its glyceride derivatives) are suitable for preparing injectables, as are natural pharmaceutically acceptable oils (such as olive oil or castor oil, especially their polyoxyethylated forms). These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants (such as Tween, Span and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms may also be used for the purpose of formulation.

The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. For tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, suitable diluents include lactose and dry corn starch. When it is necessary to use an aqueous suspension for oral use, the active ingredient is combined with an emulsifier and a suspending agent. Optionally, certain sweeteners, flavoring agents or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. These suppositories may be prepared by mixing the medicament with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

For topical application, the pharmaceutically acceptable composition provided can be formulated in the form of a suitable ointment containing an active component suspended or dissolved in one or more carriers. The carrier used for topical application of the compounds of the present invention includes, but is not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated in the form of a suitable lotion or cream containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic pH-adjusted sterile saline with or without preservatives such as benzalkonium chloride, or preferably solutions in isotonic pH-adjusted sterile saline. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated in the form of an ointment such as paraffin.

The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizers or dispersants.

Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

The amount of the compound of the invention that can be combined with carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.

It is also understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

Use of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally useful for degrading and/or inhibiting the kinase activity of one or more enzymes.

As used herein, the terms "CDK1-mediated", "CDK2-mediated", "CDK4-mediated", "CDK6-mediated", "CDK7-mediated", "CDK8-mediated" and/or "CDK9-mediated" disorders, diseases and/or conditions as used herein refer to any disease or other adverse condition in which one or more of CDK1, CDK2, CDK4, CDK6, CDK7, CDK8, CDK9, or mutants thereof are known to play a role. Therefore, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which one or more of CDK1, CDK2, CDK4, CDK6, CDK7, CDK8 and/or CDK9, or mutants thereof, are known to play a role. In some embodiments, the term "CDK2-mediated" also includes treating or lessening the severity of one or more diseases in which CCNE (e.g., CCNE1) or mutants thereof are known to play a role.

The disclosed compounds can degrade CDK2 or CDK2 and CCNE1 and are therefore suitable for treating diseases in which the underlying pathology is mediated in whole or in part by CDK2. Such diseases include cancer and other diseases with proliferative disorders. In some embodiments, the present disclosure provides for treating individuals or patients in vivo using the provided compounds or their pharmaceutically acceptable salts, so that cancerous tumor growth is inhibited. The provided compounds or their pharmaceutically acceptable salts can be used to inhibit cancerous tumor growth in the case of aberrations with activated CDK2 activity. These tumors include, but are not limited to, diseases (e.g., cancers) characterized by amplification or overexpression of CCNE1 (e.g., ovarian cancer, uterine carcinosarcoma, and breast cancer) and inactivation of p27 (e.g., breast cancer and melanoma). Therefore, in some embodiments of the method, the patient has previously been determined to have amplification of the CCNE1 gene and/or the expression level of CCNE1 in a biological sample obtained from a human individual is higher than the control expression level of CCNE1. Alternatively, the provided compounds or their pharmaceutically acceptable salts can be used in combination with other agents or standard cancer treatments as described below. In one embodiment, the present disclosure provides a method for inhibiting tumor cell growth in vitro. The method includes contacting tumor cells in vitro with a provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor cells associated with CCNE1 amplification and overexpression in an individual or patient. The method includes administering a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof to an individual or patient in need thereof.

In some embodiments, provided herein is a method of inhibiting CDK2, comprising contacting CDK2 with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of inhibiting CDK2 in a patient, comprising administering a provided compound or a pharmaceutically acceptable salt thereof to the patient.

In some embodiments, provided herein is a method of inhibiting CDK2 and CCNE1, comprising contacting CDK2 and CCNE1 with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of inhibiting CDK2 and CCNE1 in a patient, comprising administering a provided compound or a pharmaceutically acceptable salt thereof to the patient.

In some embodiments, provided herein is a method of degrading CDK2, comprising contacting CDK2 with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 in a patient, comprising administering a provided compound or a pharmaceutically acceptable salt thereof to the patient.

In some embodiments, provided herein is a method of degrading CDK2 and inhibiting CCNE1, comprising contacting CDK2 and CCNE1 with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 and inhibiting CCNE1 in a patient, comprising administering a provided compound or a pharmaceutically acceptable salt thereof to the patient.

In some embodiments, provided herein is a method of degrading CDK2 and CCNE1, comprising contacting CDK2 and CCNE1 with a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method of degrading CDK2 and CCNE1 in a patient, comprising administering a provided compound or a pharmaceutically acceptable salt thereof to the patient.

In some embodiments, provided herein is a method for treating cancer. The method comprises administering to a patient (in need thereof) a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer, characterized by amplification or overexpression of CCNE1.

In some embodiments, provided herein is a method for treating a disease or condition associated with CDK2 in a patient, comprising administering to the patient a therapeutically effective amount of a provided compound or a pharmaceutically acceptable salt thereof. In some embodiments, the disease or condition associated with CDK2 is associated with amplification of the CCNE1 gene and/or overexpression of CCNE1.

In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar et al., Proc. Natl. Acad. Sci. USA, 2009, 106(31): 12968-12973), K-Ras mutant lung cancer (see Hu, S. et al., Mol. Cancer Ther., 2015, 14(11): 2576-85), and cancer with FBW7 mutation and CCNE1 overexpression (see Takada et al., Cancer Res., 2017, 77(18): 4881-4893).

In some embodiments, the disease or disorder associated with CDK2 is squamous cell carcinoma of the lung, adenocarcinoma of the lung, adenocarcinoma of the pancreas, invasive carcinoma of the breast, carcinosarcoma of the uterus, serous cystadenocarcinoma of the ovary, adenocarcinoma of the stomach, esophageal cancer, bladder urothelial carcinoma, mesothelioma, or sarcoma.

In some embodiments, the disease or disorder associated with CDK2 is lung adenocarcinoma, breast invasive carcinoma, uterine carcinosarcoma, ovarian serous cystadenocarcinoma, or gastric adenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is adenocarcinoma, carcinoma, or cystadenocarcinoma.

In some embodiments, the disease or disorder associated with CDK2 is uterine cancer, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, bladder cancer, pancreatic cancer, or breast cancer.

In some embodiments, the disease or disorder associated with CDK2 is cancer.

In some embodiments, the cancer is characterized by amplification or overexpression of CCNE1. In some embodiments, the cancer is ovarian cancer or breast cancer characterized by amplification or overexpression of CCNE1.

In some embodiments, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that demonstrates primary or acquired resistance to CDK4/6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer.

Examples of cancers that may be treated using the compounds of the present disclosure include, but are not limited to, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or within the eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, carcinoma of the endometrium/endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, Disease), non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia), solid tumors in children, lymphocytic lymphoma, bladder cancer, kidney cancer or urethral cancer, renal pelvic cancer, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal tumors, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers (including asbestos-induced cancers), and combinations of the cancers. The compounds of the present disclosure are also suitable for treating metastatic cancers.

In some embodiments, cancers that can be treated with the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, anti-BRAF and HSP90 inhibited melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate cancer), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), head and neck squamous cell carcinoma, urothelial carcinoma (e.g., bladder), and cancers with high microsatellite instability (MSI ^high ). In addition, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

In some embodiments, cancers that can be treated using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, leukemia (such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin's lymphoma or multiple myeloma), and combinations of the aforementioned cancers.

In some embodiments, cancers that can be treated using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma (bileduct cancer), triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, mouth cancer, oral cancer, pharyngeal cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cancer, eye cancer, eye melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular cancer, urethral cancer, and ureteral cancer.

In some embodiments, the disclosed compounds are useful for treating sickle cell disease and sickle cell anemia.

In some embodiments, diseases and indications that may be treated using the disclosed compounds include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, cancers of the nervous system, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin's lymphoma, myeloproliferative diseases (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchogenic carcinoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar (bronchiolar) carcinoma, bronchial adenoma, enchondroma hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney (adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma, embryonal carcinoma, teratothelioma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma).

Exemplary liver cancers include hepatoma (eg, hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Exemplary bone cancers include, e.g., osteogenic sarcomas (e.g., osteosarcomas), fibrosarcomas, malignant fibrous histiocytomas, chondrosarcomas, Ewing's sarcoma, malignant lymphomas (reticulum cell sarcomas), multiple myeloma, malignant giant cell tumors, chordomas, osteochondromas (osteocartilaginous exostoses), benign enchondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors.

Exemplary nervous system cancers include cancers of the skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, blastomas (pinealomas), glioblastomas, glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), and spinal cord (neurofibromas, meningiomas, gliomas, sarcomas), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus (endometrial cancer), cervix (cervical cancer, preneoplastic cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, carcinoma of unspecified type), theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), and fallopian tube (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and indications that can be treated using the disclosed compounds include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial cancer.

It is believed that the provided compounds or their pharmaceutically acceptable salts may have a satisfactory pharmacological profile and promising biopharmaceutical properties, such as toxicological profile, metabolic and pharmacokinetic properties, solubility and permeability. It should be understood that the determination of appropriate biopharmaceutical properties is within the skill of the art, such as determining cytotoxicity in cells or inhibiting certain targets or pathways to determine potential toxicity.

As used herein, the term "treatment" refers to reversing, alleviating a disease or disorder as described herein or one or more symptoms thereof, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to susceptible individuals before the onset of symptoms (e.g., based on a history of symptoms and/or based on hereditary or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

The terms "subject" or "patient," which are used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates, and most preferably humans.

The phrase "therapeutically effective amount" refers to that amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, subject or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.

In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but has not yet experienced or manifested the pathology or symptoms of the disease.

Co-administration with one or more other therapeutic agents

Depending on the specific condition or disease to be treated, other therapeutic agents that are normally administered to treat that condition may also be present in the composition set of the present invention. As used herein, other therapeutic agents that are normally administered to treat a specific disease or condition are referred to as "appropriate for the disease or condition being treated."

In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and co-administering simultaneously or sequentially an effective amount of one or more other therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one other therapeutic agent. In some embodiments, the method comprises co-administering two other therapeutic agents. In some embodiments, the combination of the disclosed compounds and one or more other therapeutic agents acts synergistically.

The compounds of the invention may also be used in combination with known treatment methods, such as administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies may be provided in the form of fixed combinations or staggered or independently of one another to provide the administration of the compounds of the present invention and one or more other therapeutic compounds, or in combination with fixed combinations and one or more other therapeutic compounds. The compounds of the present invention may be administered in addition or in addition, especially in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or a combination of these for tumor treatment. As described above, long-term therapy is also possible, as is adjuvant therapy in the case of other treatment strategies. Other possible treatments are therapies that maintain the patient's state after tumor regression, or even chemoprevention, for example, for patients at risk.

One or more other therapeutic agents can be administered separately from the compounds of the present invention or compositions as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents can be part of a single dosage form, mixed with the compounds of the present invention in a single composition. If administered in a multiple dose regimen, one or more other therapeutic agents and the compounds of the present invention or compositions can be administered simultaneously, sequentially or at intervals of a certain period of time, for example, at intervals of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. In some embodiments, one or more other therapeutic agents and the compounds of the present invention or compositions are administered in a multiple dose regimen at intervals of more than 24 hours.

As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the compounds of the present invention can be administered simultaneously or sequentially with one or more other therapeutic agents in separate unit dosage forms or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising a compound of the present invention, one or more other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

The amount of the compound of the invention and one or more other therapeutic agents (in those compositions containing other therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form varies depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the compound of the invention can be administered.

In those compositions comprising one or more other therapeutic agents, the one or more other therapeutic agents and the compounds of the invention may act synergistically. Thus, the amount of one or more other therapeutic agents in such compositions may be lower than the amount required in a monotherapy utilizing only the therapeutic agent. In such compositions, one or more other therapeutic agents may be administered at a dose of between 0.01-1,000 micrograms/kg body weight/day.

The amount of one or more other therapeutic agents present in the composition of the present invention may not exceed the amount that would normally be administered in a composition comprising the therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the composition disclosed herein is within the range of about 50% to 100% of the amount normally present in a composition comprising the agent as the sole therapeutic active agent. In some embodiments, the dosage of one or more other therapeutic agents is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95% of the amount of the agent normally administered. As used herein, the phrase "normally administered" means providing an FDA-approved therapeutic agent for administration according to the FDA label insert.

The compounds of the invention or their pharmaceutical compositions may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk of clot formation or platelet activation. These adverse effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. An implantable device coated with the compounds of the invention is another embodiment of the invention.

Exemplary Additional Therapeutic Agents

In some embodiments, the one or more additional therapeutic agents are poly ADP ribose polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitor is selected from olaparib ( AstraZeneca); rucaparib ( Clovis Oncology); niraparib ( =In the pipeline, the first-line candidates are FDA-approved sham-treated leukemia patients with leukemia who were previously treated with sham-treated leukemia patients. The first-line candidates are FDA-approved sham-treated leukemia patients with leukemia who were previously treated with sham-treated leukemia patients.

In some embodiments, the one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat ( Merck); romidepsin ( Celgene); panobinostat ( Novartis); belinostat ( Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

In some embodiments, the one or more other therapeutic agents are CDK inhibitors, such as CDK4/CDK6 inhibitors. In some embodiments, the CDK 4/6 inhibitor is selected from palbociclib ( Pfizer); ribociclib ( Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

In some embodiments, the one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib ( Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech/Roche), pictilisib (GDC-0941, Genentech/Roche), copanlisib (BAY806946, Bayer), duvelisib (formerly IPI-145, Infinity Pharmaceuticals), PQR309 (Piqur Therapeutics, Switzerland), and TGR1202 (formerly RP5230, TG Therapeutics).

In some embodiments, the one or more other therapeutic agents are platinum-based therapeutic agents, also known as platinum compounds (platins). Platinum causes cross-linking of DNA, such that it primarily inhibits DNA repair and/or DNA synthesis in rapidly reproducing cells (such as cancer cells). In some embodiments, the platinum-based therapeutic agent is selected from cisplatin ( Bristol-Myers Squibb); carboplatin ( Bristol-Myers Squibb; Teva; Pfizer; oxaliplatin Sanofi-Aventis); nedaplatin ( =These drugs include sirolimus (Shionogi); picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

In some embodiments, the one or more additional therapeutic agents are taxane compounds, which cause disruption of microtubules, which is necessary for cell division. In some embodiments, the taxane compound is selected from paclitaxel ( Bristol-Myers Squibb), docetaxel ( Sanofi-Aventis; Sun Pharmaceuticals), albumin-bound paclitaxel ( Abraxis/Celgene), cabazitaxel ( Sanofi-Aventis) and SID530 (SK Chemicals, Co.) (NCT00931008).

In some embodiments, the one or more additional therapeutic agents are nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

In some embodiments, the nucleoside inhibitor is selected from trabectedin (a guanidating agent, Janssen Oncology); Methylchlor (alkylating agent, Aktelion Pharmaceuticals); vincristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics); Temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazene-1-yl)-imidazole-4-carboxamide (MTIC) Merck); Cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); Lomustine (alkylating agent, Bristol-Myers Squibb; NextSource Biotechnology); Azacitidine (a pyrimidine nucleoside analog of cytidine, Celgene); omacetaxine mepesuccinate (omacetaxine mepesuccinate) (protein synthesis inhibitor, Teva Pharmaceuticals); Asparaginase Erwinia chrysanthemi (an enzyme that consumes asparagine, Lundbeck; EUSA Pharma); Eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Eisai); Cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Sanofi-Aventis); capacetrine (thymidylate synthase inhibitor, Genentech); bendamustine (a bifunctional mustard derivative believed to form interstrand DNA crosslinks, Cephalon/Teva); ixabepilone (a semisynthetic analog of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent, Bristol-Myers Squibb); Nelarabine (a prodrug of a deoxyguanosine analog, a nucleoside metabolic inhibitor, Novartis); clorafabine (ribonucleotide reductase inhibitor prodrug, competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analogs and thymidine phosphorylase inhibitors, Taiho Oncology).

In some embodiments, the one or more additional therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors suitable for use in the present invention include: bevacizumab ( Genentech/Roche), an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly), an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as a VEGF trap ( Regeneron/Sanofi). VEGFR inhibitors, such as regorafenib ( Bayer); vandetanib ( AstraZeneca); axitinib ( Pfizer); and lenvatinib ( Eisai); Raf inhibitors, such as sorafenib ( Bayer and Onyx); dabrafenib ( Novartis); and vemurafenib ( Genentech/Roche); MEK inhibitors, such as cobimetanib ( Exelexis/Genentech/Roche); trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib ( Novartis); nilotinib ( Novartis); dasatinib ( Bristol-Myers Squibb); bosutinib ( Pfizer); and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca; erlotinib ( Genentech/Roche/Astellas); Lapatinib ( Novartis); afatinib ( Boehringer Ingelheim); osimertinib (targets activated EGFR, AstraZeneca); and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Axis); and multikinase inhibitors, such as sunitinib ( Pfizer); pazopanib ( Novartis); ALK inhibitors, such as crizotinib ( Pfizer); ceritinib ( Novartis); and alectinib ( Genentech/Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib ( Pharmacyclics/Janssen); and Flt3 receptor inhibitors, such as midostaurin ( Novartis).

Other kinase inhibitors and VEGF-R antagonists in development and useful in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer/Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Microchip Biopharmaceuticals); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib ( IY5511, Il-Yang Pharmaceuticals, S.Korea); ruxolitinib ( Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Axis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen/Takeda).

In some embodiments, the one or more additional therapeutic agents are mTOR inhibitors, which inhibit cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus ( Novartis), temsirolimus ( Pfizer) and sirolimus ( Pfizer).

In some embodiments, the one or more additional therapeutic agents are proteasome inhibitors. Approved proteasome inhibitors suitable for use in the present invention include bortezomib ( Takeda); carfilzomib( Amgen); and ixazomib ( Takeda).

In some embodiments, the one or more additional therapeutic agents are growth factor antagonists, such as antagonists of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or their receptors (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab ( Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab ( Eli Lilly); necitumumab ( Eli Lilly); panitumumab ( Amgen); and osimertinib (targeting activated EGFR, AstraZeneca).

In some embodiments, the one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane ( Pfizer); Anastrozole ( AstraZeneca) and Letrozole ( Novartis).

In some embodiments, one or more of the additional therapeutic agents is a hedgehog pathway antagonist. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib ( Sun Pharmaceuticals); and vismodegib ( Genentech), both for the treatment of basal cell carcinoma.

In some embodiments, the one or more additional therapeutic agents are folate inhibitors. Approved folate inhibitors suitable for use in the present invention include pemetrexed ( Eli Lilly).

In some embodiments, the one or more additional therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors under investigation for use in the present invention include mogamulizumab ( Kyowa Hakko Kirin, Japan).

In some embodiments, one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors under study that can be used in the present invention include AG120 (Cell Gene; NCT02677922); AG221 (Cell Gene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

In some embodiments, one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors under investigation that can be used in the present invention include AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

In some embodiments, the one or more additional therapeutic agents is a glutaminase inhibitor. Glutaminase inhibitors under investigation for use in the present invention include CB-839 (Calila Biosciences).

In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab ( Genentech/Biogen Idec); ofatumumab (anti-CD20, GlaxoSmithKline); obinutuzumab (anti-CD20, Genentech); ibritumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Janssen Biotech); dinutuximab (anti-glycolipid GD2, United Therapeutics); trastuzumab (anti-HER2, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Genentech); and pertuzumab (anti-HER2, Genentech); and brentuximab vedotin (anti-CD30 drug conjugate, Seattle Genetics).

In some embodiments, the one or more additional therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors suitable for use in the present invention include irinotecan ( Merrimack Pharmaceuticals); topotecan ( GlaxoSmithKline). Topoisomerase inhibitors under investigation for use in the present invention include pixantrone ( (CTI Biopharma).

In some embodiments, one or more other therapeutic agents are anti-apoptotic proteins, such as inhibitors of BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax ( AbbVie/Genentech) and blinatumomab ( Other therapeutic agents that target apoptotic proteins that have been clinically tested and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

In some embodiments, the one or more additional therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors suitable for use in the present invention include enzalutamide ( Astellas/Medivex); approved androgen synthesis inhibitors include abiraterone ( Centocor/Ortho); approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degaralix, Ferring Pharmaceuticals).

In some embodiments, the one or more additional therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs suitable for use in the present invention include raloxifene ( Eli Lilly).

In some embodiments, the one or more additional therapeutic agents are bone resorption inhibitors. Approved therapeutic agents that inhibit bone resorption are Denosumab ( Amgen), an antibody that binds to RANKL, preventing binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which modulates bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid ( Novartis).

In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between two primary p53 inhibitory proteins MDMX and MDM2. Inhibitors of p53 inhibitory proteins under study that can be used in the present invention include ALRN-6924 (Aileron), a cleavage peptide that is allosterically bound to MDMX and MDM2 and interferes with the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS) and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

In some embodiments, one or more other therapeutic agents are inhibitors of transforming growth factor beta (TGF-β or TGFβ). TGF-β protein inhibitors under investigation for use in the present invention include NIS793 (Novartis), an anti-TGF-β antibody being tested in the clinic for the treatment of various cancers (NCT02947165) including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer. In some embodiments, the TGF-β protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169), renal cell carcinoma (NCT00356460), and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the other therapeutic agent is a TGF-β trap as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. A therapeutic compound currently in clinical trials for the treatment of solid tumors is M7824 (Merck - formerly MSB0011459X), a bispecific anti-PD-L1/TGFβ trap compound (NCT02699515); and (NCT02517398). M7824 comprises a fully human IgG1 antibody directed against PD-L1 fused to the extracellular domain of human TGF-β receptor II, which serves as a TGFβ "trap".

In some embodiments, the one or more additional therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types associated with the metastatic ability of cancer cells.

In some embodiments, one or more other therapeutic agents are anti-proliferative compounds. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target/reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists (gonadorelin agonist); anti-androgen; methionine aminopeptidase inhibitor; matrix metalloproteinase inhibitor; bisphosphonate; biological response modifier; antiproliferative antibody; heparanase inhibitor; inhibitor of Ras oncogenic isoform; telomerase inhibitor; proteasome inhibitor; compounds for the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, TEMODAL CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide Kinesin inhibitors such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZd ₆ 244 from AstraZeneca, PD181461 from Pfizer, and leucovorin.

As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and especially non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name AROMASIN ^TM . Formestane is sold under the trade name LENTARON ^TM . Fadrozole is sold under the trade name AFEMA ^TM . Anastrozole is sold under the trade name ARIMIDEX ^™ . Letrozole is sold under the trade name FEMARA ^™ or FEMAR ^™ . Aminoglutide is sold under the trade name ORIMETEN ^™ . The combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly suitable for the treatment of hormone receptor positive tumors, such as breast tumors.

As used herein, the term "anti-estrogen" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name NOLVADEX ^TM . Raloxifene hydrochloride is sold under the trade name EVISTA ^TM . The fulvestrant of the trade name FASLODEX ^TM can be used. Combinations of the present invention comprising chemotherapeutic agents as anti-estrogen are particularly suitable for treating estrogen receptor positive tumors, such as breast tumors.

As used herein, the term "antiandrogen" refers to any substance capable of inhibiting the biological action of androgens and includes, but is not limited to, bicalutamide (CASODEX ^™ ). As used herein, the term "gonadotropin agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin, available under the trade name ZOLADEX ^™ , can be administered.

As used herein, the term "topoisomerase I inhibitors" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form in which it is sold, for example, under the trademark CAMPTOSAR ^™ . Topotecan is sold under the trade name HYCAMPTIN ^™ .

As used herein, the term "topoisomerase II inhibitors" include, but are not limited to, anthracyclines such as doxorubicin (including lipid formulations such as CAELYX ^™ ), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name ETOPOPHOS ^™ . Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name ACRIBLASTIN ^™ or ADRIAMYCIN ^™ . Epirubicin is sold under the trade name FARMORUBICIN ^™ . Idacycline is sold under the trade name ZAVEDOS ^™ . Mitoxantrone is sold under the trade name NOVANTRON ^™ .

The term "microtubule active agent" refers to microtubule stabilizing, microtubule destabilizing compounds and microtubule polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate and vinorelbine; discodermolide; cochicine and epothilone and its derivatives. Pacific paclitaxel is sold under the trade name TAXOL ^TM . Docetaxel is sold under the trade name TAXOTERE ^TM . Vinblastine sulfate is sold under the trade name VINBLASTIN RP ^TM . Vincristine sulfate is sold under the trade name FARMISTIN ^TM .

As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name CYCLOSTIN ^™ . Ifosfamide is sold under the trade name HOLOXAN ^™ .

The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylase and have antiproliferative activity. Such compounds include, but are not limited to, suberoylanilide hydroxamic acid (SAHA).

The term "anti-neoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is sold under the trade name XELODA ^™ . Gemcitabine is sold under the trade name GEMZAR ^™ .

The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cisplatin (cis-platin/cisplatinum) and oxaliplatin. Carboplatin can be administered, for example, in the form in which it is sold, for example, under the trademark CARBOPLAT ^™ . Oxaliplatin can be administered, for example, in the form in which it is sold, for example, under the trademark ELOXATIN ^™ .

As used herein, the term "compounds that target protein or lipid kinases/reduce their activity or target protein or lipid phosphatase activity/reduce their activity; or other anti-angiogenic compounds" includes, but is not limited to: protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target platelet-derived growth factor receptor (PDGFR), reduce or inhibit its activity, such as compounds that target PDGFR, reduce or inhibit its activity, especially compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target fibroblast growth factor receptor (FGFR), reduce or inhibit its activity; c) compounds that target insulin-like growth factor receptor I (IGF-IR), reduce or inhibit its activity, such as compounds that target IGF-IR, reduce or inhibit its activity, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factor; d) antibodies that target Trk receptor tyrosine kinase family, compounds that reduce or inhibit their activity, or ephrin B4 inhibitors; e) compounds that target the AxI receptor tyrosine kinase family, compounds that reduce or inhibit their activity; f) compounds that target the Ret receptor tyrosine kinase, compounds that reduce or inhibit their activity; g) compounds that target the Kit/SCFR receptor tyrosine kinase, compounds that reduce or inhibit their activity, such as imatinib; h) compounds that target the C-kit receptor tyrosine kinase (which is part of the PDGFR family), compounds that reduce or inhibit their activity, such as compounds that target c-Kit Receptor tyrosine kinase family, compounds that reduce or inhibit their activity, especially compounds that inhibit c-Kit receptor, such as imatinib; i) compounds that target members of the c-Abl family, their gene fusion products (e.g., BCR-Abl kinase) and mutants, compounds that reduce or inhibit their activity, such as compounds that target c-Abl family members and their gene fusion products, reduce or inhibit their activity, such as N-phenyl-2-pyrimidine-amine derivatives (such as imatinib or nilotinib (AMN107)), PD180970, AG957, NSC 680410, PD173955 or dasatinib (BMS-354825) from ParkeDavis; j) members of protein kinase C (PKC) and Raf family of serine/threonine kinases, MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family and/or members of cyclin-dependent kinase family (CDK), compounds that reduce or inhibit their activity, including staurosporine derivatives such as midostaurin; examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine, Ilmofosine, RO 318220 and RO320432, GO 6976, lsis 3521, LY333531/LY379196, isochinoline compounds, FTIs, PD184352 or QAN697 (a P13K inhibitor) or AT7519 (a CDK inhibitor); k) targeted protein tyrosine kinase inhibitors, compounds that reduce or inhibit their activity, such as targeted protein tyrosine kinase inhibitors, compounds that reduce or inhibit their activity, including imatinib mesylate (GLEEVEC ^™ ) or tyrphostin, such as tyrphostin A23/RG-50810, AG 99, tyrphostin AG 213, tyrphostin AG 1748, tyrphostin AG 490, tyrphostin B44, tyrphostin B44 (+) enantiomer, tyrphostin AG 555, AG 494, tyrphostin AG 556, AG957 and adaphostin (adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds targeting the epidermal growth factor family of receptor tyrosine kinases (EGFR ₁ ErbB2, ErbB3, ErbB4, in the form of homodimers or heterodimers) and mutants thereof, compounds that reduce or inhibit their activity, such as compounds targeting the epidermal growth factor receptor family, reducing or inhibiting their activity, especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members (such as EGF receptors ErbB2, ErbB3 and ErbB4) or bind to EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180, trastuzumab (HERCEPTIN ^™ ), cetuximab (ERBITUX ^™) ), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target c-Met receptors, reduce or inhibit their activity, such as compounds that target c-Met, reduce or inhibit their activity, especially compounds that inhibit the kinase activity of c-Met receptors, or antibodies targeting the extracellular domain of c-Met or binding to HGF; n) compounds that target one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK) and reduce or inhibit their kinase activity, including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480 , TG-101348, tofacitinib and ruxolitinib; o) compounds that target PI3 kinase (PI3K), reduce or inhibit its kinase activity, including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-46 91502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and q) compounds that target the Hedgehog (Hh) or Smoothened receptor (SMO) pathways, reduce or inhibit their signal transduction effects, including but not limited to cyclopamine, vimodegib, itraconazole, erismodegib and IPI-926 (saridegib).

The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity on one or more enzymes in the phosphatidylinositol-3-kinase family, including but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101 and p87. Examples of PI3K inhibitors suitable for use in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparcoxib, picoxib, PF-4691502, BYL-719, datoxib, XL-147, XL-765, and idecoxib.

The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), Bcl-2/Bcl-xL dual inhibitor (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan) and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptide mimetic.

As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

The term "SYK inhibitor" as used herein includes, but is not limited to, compounds having inhibitory activity on spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

Further examples of BTK inhibiting compounds and conditions that can be treated by such compounds in combination with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

Further examples of SYK inhibiting compounds and conditions that may be treated by such compounds in combination with the compounds of the invention may be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

Other examples of PI3K inhibitory compounds and conditions that can be treated by such compounds in combination with the compounds of the invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

Further examples of JAK inhibitory compounds and conditions that may be treated by such compounds in combination with the compounds of the invention may be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

Other anti-angiogenic compounds include compounds with another mechanism of activity (eg, activity unrelated to protein or lipid kinase inhibition), such as thalidomide (THALOMID ^™ ) and TNP-470.

Examples of proteasome inhibitors suitable for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

Compounds that target protein or lipid phosphatases, decrease or inhibit their activity are, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ-tocopherol or δ-tocopherol, or α-γ-tocotrienol or δ-tocotrienol.

The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (CELEBREX ^™ ), rofecoxib (VIOXX ^™ ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2'-chloro-6'-fluorophenylamino)phenylacetic acid, lumiracoxib.

As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is sold under the trade name DIDRONEL ^TM . Clodronic acid is sold under the trade name BONEFOS ^TM . Tiludronic acid is sold under the trade name Skelid ^TM . Pamidronic acid is sold under the trade name AREDIA ^TM . Alendronic acid is sold under the trade name FOSAMAX ^TM . Ibandronic acid is sold under the trade name BONDRANAT ^TM . Risedronic acid is sold under the trade name ACTONEL ^TM . Zoledronic acid is sold under the trade name ZOMETA ^TM . The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus. Everolimus (CERTICAN ^™ ), CCI-779, and ABT578.

As used herein, the term "heparinase inhibitor" refers to a compound that targets heparin sulfate, reduces or inhibits its degradation. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphatic mediator or interferon.

As used herein, the term "inhibitor of Ras oncogenic isoforms (such as H-Ras, K-Ras or N-Ras)" refers to a compound that targets Ras, reduces or inhibits its oncogenic activity; for example, a "farnesyltransferase inhibitor", such as L-744832, DK8G557 or R115777 (ZARNESTRA ^™ ). As used herein, the term "telomerase inhibitor" refers to a compound that targets telomerase, reduces or inhibits its activity. Compounds that target telomerase, reduce or inhibit its activity are especially compounds that inhibit the telomerase receptor, such as telomestatin.

As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase, reduces or inhibits its activity. Compounds that target methionine aminopeptidase, reduce or inhibit its activity include but are not limited to bengamide or its derivatives.

As used herein, the term "proteasome inhibitor" refers to a compound that targets proteasome, decreases or inhibits its activity. Compounds that target proteasome, decreases or inhibits its activity include, but are not limited to, bortezomib (VELCADE ^™ ) and MLN341.

As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptide mimetic and non-peptide mimetic inhibitors, tetracycline derivatives, such as the hydrooxalamic acid ester peptide mimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and busulfan; and ALK inhibitors, which are compounds that target, reduce or inhibit anaplastic lymphoma kinase.

Compounds that target FMS-like tyrosine kinase receptor (Flt-3R), reduce or inhibit its activity are particularly compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity, and degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG) (a geldanamycin derivative), other geldanamycin-related compounds, radicicol and HDAC inhibitors.

As used herein, the term "anti-proliferative antibodies" include, but are not limited to, trastuzumab (HERCEPTIN ^™ ), trastuzumab-DM1, erbitux, bevacizumab (AVASTIN ^™ ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be combined with standard leukemia therapies, in particular, with therapies used to treat AML. Specifically, the compounds of the present invention can be used in combination with, for example, farnesyl transferase inhibitors and/or other drugs suitable for treating AML, such as daunomycin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idamycin, carboplatin and PKC412.

Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Targeted histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), compounds that reduce or inhibit their activity inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228). , Trichostatin A and compounds disclosed in US 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, the somatostatin receptor antagonist refers to a compound that targets, treats or inhibits the somatostatin receptor, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. The term "ionizing radiation" mentioned above and below means ionizing radiation in the form of electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha particles and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology, Devita et al., eds., 4th ed., Vol. 1, pp. 248-275 (1993).

Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to fight ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

Also specifically included are those compounds, proteins or monoclonal antibodies to VEGF, such as 1-(4-chlorophenylamino)-4-(4-pyridinylmethyl)piperazine or a pharmaceutically acceptable salt thereof; 1-(4-chlorophenylamino)-4-(4-pyridinylmethyl)piperazine succinate; ANGIOSTATIN ^™ ; ENDOSTATIN ^™ ; anthranilic acid amide; ZD4190; Zd ₆ 474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab; VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (AVASTIN ^™ ).

Photodynamic therapy, as used herein, refers to therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatments using compounds such as VISUDYNE ^™ and porfimer sodium.

As used herein, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

Implants containing corticosteroids include compounds such as fluocinolone and dexamethasone.

Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphomediators or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

The structures of active compounds identified by code numbers, generic or trade names can be obtained from the official standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

Exemplary Immuno-Oncology Agents

In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates and/or upregulates an immune response in a subject. In some embodiments, the administration of an immuno-oncology agent together with the compounds of the invention has a synergistic effect in treating cancer.

The immuno-oncology agent can be, for example, a small molecule drug, an antibody, or a biological molecule or a small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized or human antibody.

In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in expansion of antigen-specific T cell responses.

Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA) and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to homologous TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L, TRAILR1/DR4, TRAILR2/DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL ,TWEAKR/Fn14, TWEAK, BAFFR, EDAR, TROY, NGFR.

In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (eg, IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation so as to stimulate an immune response.

In some embodiments, the combination of the compounds of the invention and immuno-oncology agents can stimulate T cell responses. In some embodiments, the immuno-oncology agent is: (i) an antagonist (e.g., an immune checkpoint inhibitor) of a protein that inhibits T cell activation, such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 (WO11/70024, WO11/107553, WO11/131407, WO13/87699, WO13/119716, WO13/132044) or FPA-008 (WO11/140249; WO13169264; WO14/036357).

In some embodiments, the immuno-oncology agent is selected from: agonists that bind positive co-stimulatory receptors; blockers that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells; agents that overcome unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1/PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing/preventing T cell energy or exhaustion); and agents that trigger innate immune activation and/or inflammation at the tumor site.

In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012/145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, referred to as AMP-224.

In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010/077634), durvalumab (MEDI4736), BMS-936559 (WO2007/005874), and MSB0010718C (WO2013/79174).

In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10/19570, WO14/08218) or IMP-731 or IMP-321 (WO08/132601, WO009/44273).

In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonist CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12/32433).

In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonist GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006/105021, WO009/009116) or MK-4166 (WO11/028683).

In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech/Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906/KD108 (Phytoceutica); an enzyme that degrades kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Pharmaceuticals); Therapeutics); and NLG-919 (WO09/73620, WO009/1156652, WO11/56652, WO12/142237).

In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonist OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06/029879).

In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonist CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO 11/109400).

In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, icadolstat, epratuzumab, indomod, inotuzumab, intelumumab , ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofavumab, olatatumab, pedrizumab, pilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in an increased number of tumor tissue structures, including some tumor types that have not been conventionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. Anti-PD-1 antibody nivolumab Bristol-Myers Squibb's ANTIANGIO-4538 (also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who experience disease progression during or after prior anti-angiogenic therapy.

In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide ( Celgene; lenalidomide ( Celgene; ingenol mebutate ( LEO Pharma).

In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon/Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex/Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous and nodular lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from an oncolytic virus therapy such as pexastimogene devacirepvec (PexaVec/JX-594, SillaJen/formerly known as Jennerex Biotherapeutics), a thymidine kinase (TK)-deficient poxvirus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( =Oncolytics Biotech), a variant of the reovirus that does not replicate in cells without RAS activation in multiple cancers including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic cancer (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an engineered reovirus that does not replicate in cells without RAS activation in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax/formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68/GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal)/β-glucuronidase or β-gal/human sodium iodide symporter (hNIS), respectively, studied in peritoneal carcinoma (NCT01443260), fallopian tube cancer, and ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

In some embodiments, the immuno-oncology agent is selected from JX-929 (Xillazhen/formerly Zhenlerui Biopharmaceuticals), a TK- and acne growth factor-deficient acne virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Tagwa/formerly Angks), peptide-based immunotherapeutics that target difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus called: Ad5/3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express a glycoprotein designed to produce antigen-specific CD8 ⁺ Antigens to which T cells respond.

In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

The following CAR has been constructed, which consists of a binding domain that can be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, and an intracellular domain as the functional end of a T cell receptor (TCR), such as a CD3-ζ signaling domain from a TCR that can generate an activation signal in a T lymphocyte. Upon antigen binding, such CARs are connected to the endogenous signaling pathway in the effector cell and generate an activation signal similar to that triggered by the TCR complex.

For example, in some embodiments, the CAR-T cell is one of those described in U.S. Pat. No. 8,906,682 (June et al.; the entire contents of which are incorporated herein by reference), which discloses CAR-T cells engineered to include an extracellular domain having an antigen binding domain (such as a domain that binds to CD19) fused to an intracellular signaling domain of a T cell antigen receptor complex ζ chain (such as CD3ζ). When expressed in T cells, the CAR is able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials using CAR-T in various indications are in progress. [https://clinicaltrials.gov/ct2/results?term=chimeric+antigen+receptors&pg=1].

In some embodiments, the immunostimulator is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of innate immune cell subsets expressing IL-17 (such as NK cells). In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG, which is being studied for B cells, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which are being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varitumumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102/BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences) Sciences), an anti-MMP9 antibody; MK-4166 (Merck), an anti-GITR monoclonal antibody.

In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15 class immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis/Admune), a fusion complex composed of a synthetic form of endogenous IL-15 and a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

In some embodiments, the immuno-oncology agent is selected from the immuno-oncology agents described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology", Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry Adams et al. In some embodiments, the immuno-oncology agent is a small molecule selected from those small molecules of the target immuno-oncology target listed in Table 2 of Jerry Adams et al. In some embodiments, the immuno-oncology agent is a small molecule selected from those small molecule agents listed in Table 2 of Jerry Adams et al.

In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent that targets a pathway as described in Peter L. Toogood.

In some embodiments, the immuno-oncology agent is selected from Sandra L. Ross et al., "Bispecific T cell engagers Antibody constructs can mediate the killing of adjacent tumor cells (Bispecific T cellengager Antibody constructs can mediate bystander tumor cell killing), "Public Library of Science - Comprehensive (PLoS ONE) 12 (8): e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager Antibody constructs. In some embodiments, bispecific T cell engagers The antibody construct is a CD19/CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR/CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager Antibody constructs activate T cells. In some embodiments, bispecific T cell engagers The antibody construct activates T cells, releasing cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, inducing bystander cell lysis. In some embodiments, the bystander cells are in a solid tumor. In some embodiments, the lysed bystander cells are near Activated T cells. In some embodiments, the adjacent cells include tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the adjacent cells include EGFR negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1/PD1 axis and/or CTLA4. In some embodiments, the immuno-oncology agent is a tumor-infiltrating T cell that is expanded ex vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigens (TAA).

Exemplary Immune Checkpoint Inhibitors

In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

The term "checkpoint inhibitor" as used herein refers to an agent that is useful for preventing cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immune destruction is called "T cell exhaustion", which is caused by long-term exposure to antigens that cause upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints to prevent uncontrolled immune responses.

PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223) and other receptors are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to indicate whether cell cycle progression and other intracellular signaling processes will continue.

In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby overriding the tumor's ability to suppress the host's anti-tumor immune response.

In some embodiments, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from the following: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand selected from the following checkpoint proteins: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In another aspect, the vaccine is a dendritic cell (DC) vaccine.

Check point inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors, or may include antibodies or antigen binding fragments thereof that are bound to immune check point receptors and block or inhibit immune check point receptors, or antibodies that are bound to immune check point receptor ligands and block or inhibit the ligands. Illustrative check point molecules that can be targeted to block or inhibit include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 family of molecules and expressed in all NK, γδ and memory CD8 ⁺ (αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of: nivolumab Ipilimumab Pedrizumab In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb); Pedrizumab (anti-PD-1 antibody, Merck); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb); Durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

In some embodiments, the checkpoint inhibitor is selected from the group consisting of: lambrolizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, levolumab, IPH2101, pembrolizumab and tremelimumab.

In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer/Merck), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; AstraZeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for multiple indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic duct adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Taishanuo) is an anti-TIM-3 antibody studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody studied in advanced malignancies (NCT02608268).

In some embodiments, the checkpoint inhibitor is an inhibitor of a T cell immune receptor with an Ig domain and an ITIM domain or TIGIT (an immune receptor on certain T cells and NK cells). TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is being studied in malignancies (NCT03005782). IMP321 (Immutep S.A.) is a LAG-3-Ig fusion protein that is being studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833), and metastatic breast cancer (NCT00349934).

Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists studied in clinical trials include: PF-04518600/PF-8600 (Pfizer), an agonist anti-OX40 antibody in metastatic renal cancer (NCT03092856) and advanced cancer and tumors (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonist anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune/Asterixene), an advanced solid tumor (NCT02528357); CT02318394 and NCT02705482); MEDI6469, an agonist anti-OX40 antibody (Medimune/Asterixeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody in advanced cancer (NCT02737475).

Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists studied in clinical trials include: utomilumab (PF-05082566, Pfizer), a diffuse large B-cell lymphoma (NCT02951156) and advanced cancer and tumors (NCT02554812 and NCT05082566) in the agonist anti-CD137 antibody; Urelumab (BMS-663513, Bristol-Myers Squibb), a melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981) in the agonist anti-CD137 antibody; and CTX-471 (Compass Therapeutics), a metastatic or locally advanced malignant disease in the agonist anti-CD137 antibody.

Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists studied in clinical trials include: varimumab (CDX-1127, Celldex Therapeutics), an agonist anti-CD27 antibody in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

Checkpoint inhibitors useful in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include: TRX518 (Leap Therapeutics), an agonist anti-GITR antibody in malignant melanoma and other solid malignancies (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonist anti-GITR antibody in solid tumors and lymphomas (NCT 02740270); INCAGN01876 (Incyte/Aginas), an agonist anti-GITR antibody in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimine/Astrinica), a human IgG1 Fc domain-enhancing hexameric GITR ligand molecule.

Checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists studied in clinical trials include: MEDI-570 (Medimine), an agonist anti-ICOS antibody in lymphoma (NCT02520791); GSK3359609 (Merck), an agonist anti-ICOS antibody in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonist anti-ICOS antibody in Phase 1 (NCT02904226).

Checkpoint inhibitors useful in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include levofloxacin (IPH2102/BMS-986015, Innate Pharmaceuticals/Bristol-Myers Squibb), an anti-KIR antibody in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharmaceuticals) in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharmaceuticals), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2) in lymphoma (NCT02593045).

Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47/SIRPa inhibitors being studied in clinical trials include: ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and prevents CD47/SIRPa-mediated signaling in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a Phase 1 clinical trial (NCT02890368 and NCT02663518) that is produced by linking the N-terminus of the CD47 binding domain of SIRPa to the Fc domain of human IgG1, works by binding to human CD47 and preventing it from delivering its "do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis (do not allow phagocytosis ( eat) signal to macrophages; CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors studied in clinical trials include MEDI9447 (MediMuein), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING studied in clinical trials include: MK-1454 (Merck), an agonist synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech/Novartis), an agonist synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).

Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors studied in clinical trials include: pexidartinib (PLX3397, Plexxikon), a small molecule inhibitor of CSF1R in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710), as well as melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY30 22855, Eli Lilly), an anti-CSF-1R antibody in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide, Novartis), an orally effective inhibitor of CSF1R in advanced solid tumors (NCT02829723).

Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors studied in clinical trials include monazumab (IPH2201, Innatech Pharmaceuticals), an anti-NKG2A antibody in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pirizumab.

example

abbreviation

Ac：Acetyl

AcOH: acetic acid

ACN: Acetonitrile

Ad：Adamantyl

AIBN: 2,2'-azobisisobutyronitrile

Anhyd: Anhydrous

Aq: aqueous solution

B ₂ Pin ₂ ：Bis(pinacol)diboron-4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane)

BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

BH ₃ : Borane

Bn: benzyl

Boc: tert-butyloxycarbonyl

Boc ₂ O: di-tert-butyl dicarbonate

BPO: Benzoyl peroxide

ⁿ BuOH: n-butanol

CDI: Carbonyldiimidazole

COD: Cyclooctadiene

d: day

DABCO: 1,4-diazabicyclo[2.2.2]octane

DAST: Diethylaminosulfur trifluoride

dba: dibenzylideneacetone

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE: 1,2-dichloroethane

DCM: dichloromethane

DEA: Diethylamine

DHP: Dihydropyran

DIBAL-H: Diisobutylaluminum hydride

DIPA: Diisopropylamine

DIPEA or DIEA: N,N-diisopropylethylamine

DMA: N,N-dimethylacetamide

DME: 1,2-dimethoxyethane

DMAP: 4-dimethylaminopyridine

DMF: N,N-dimethylformamide

DMP: Dess-Martin Periodinane

DMSO-dimethyl sulfoxide

DPPA: diphenylphosphoryl azide

dppf: 1,1'-bis(diphenylphosphino)ferrocene

EDC or EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

ee: enantiomeric excess

ESI: Electrospray ionization

EA: Ethyl acetate

EtOAc: ethyl acetate

EtOH: ethanol

FA: Formic acid

h or hr: hours

HATU: N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate

HCl: hydrochloric acid

HPLC: High Performance Liquid Chromatography

HOAc: acetic acid

IBX: 2-iodooxybenzoic acid

IPA: Isopropyl alcohol

KHMDS: Potassium hexamethyldisilazide

K ₂ CO ₃ : Potassium carbonate

LAH: Lithium Aluminum Hydride

LDA: lithium diisopropylamide

m-CPBA: meta-chloroperbenzoic acid

M: Moore

MeCN: Acetonitrile

MeOHMethanol

Me ₂ S: dimethyl sulfide

MeONa: Sodium methoxide

MeI: methyl iodide

min: minutes

mL: milliliters

mM: millimole

mmol: millimole

MPa: Megapascal

MOMCl: Methyl chloromethyl ether

MsCl: Methanesulfonyl chloride

MTBE: Methyl tert-butyl ether

nBuLi: n-butyllithium

NaNO ₂ ：Sodium nitrite

NaOH: Sodium hydroxide

Na ₂ SO ₄ : Sodium sulfate

NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide

NFSI: N-Fluorobenzenesulfonimide

NMO: N-methylmorpholine N-oxide

NMP: N-methylpyrrolidine

NMR: Nuclear Magnetic Resonance

℃: Celsius

Pd/C: Palladium/Carbon

Pd(OAc) ₂ : Palladium acetate

PBS: Phosphate buffered saline

PE: Petroleum ether

POCl ₃ : Phosphorus oxychloride

PPh ₃ : triphenylphosphine

PyBOP: (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate

Rel: relative

R.T. or rt: room temperature

sat: saturated

SEMCl: chloromethyl-2-trimethylsilylethyl ether

SFC: Supercritical Fluid Chromatography

SOCl ₂ : Sulfur dichloride

tBuOK: Potassium tert-butoxide

TBAB: Tetrabutylammonium bromide

TBAI: Tetrabutylammonium iodide

TEA: triethylamine

Tf: trifluoromethanesulfonate

TfAA, TFMSA or Tf ₂ O: trifluoromethanesulfonic anhydride

TFA: trifluoroacetic acid

TIPS: triisopropylsilyl

THF: Tetrahydrofuran

THP: Tetrahydropyran

TLC: Thin layer chromatography

TMEDA: Tetramethylethylenediamine

pTSA: p-Toluenesulfonic acid

wt: weight

Xantphos: 4,5-bis(diphenylphosphine)-9,9-dimethyldibenzopyran

General synthetic method

The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. If not otherwise mentioned, all evaporations are carried out under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (=20-133 mbar). The structures of the final products, intermediates, and starting materials can be confirmed by standard analytical methods (e.g., microanalysis) and spectral characteristics (e.g., MS, IR, NMR, as exemplified below). The abbreviations used are conventional abbreviations in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to those of ordinary skill in the art (Houben-Weyl 4th edition 1952, Methods of Organic Synthesis, Thieme, Vol. 21). In addition, the compounds of the present invention can be produced by organic synthesis methods known to those of ordinary skill in the art as shown in the following examples.

Unless otherwise stated, all reactions were performed under nitrogen or argon.

Proton NMR ( ^1H NMR) was performed in deuterated solvents. In certain compounds disclosed herein, one or ^more1H shifts overlap with residual protein solvent signals; these signals are not reported in the experiments presented below.

Table 3: Analytical instruments

For acidic LCMS data: LCMS was recorded on an Agilent 1200 series LC/MSD or Shimadzu LCMS2020 equipped with electrospray ionization and quadrupole MS detector [ES+ve to give MH ⁺ ] and equipped with a Chromolith FlashRP-18e 25×2.0 mm, eluting with 0.0375 vol% TFA/water (solvent A) and 0.01875 vol% TFA/acetonitrile (solvent B). Other LCMS were recorded on an Agilent 1290 Infinity RRLC attached to an Agilent 6120 Mass detector. The column used may be a BEH C18 50×2.1 mm, 1.7 micron. The column flow was 0.55 ml/min, and the mobile phase used (A) may include 2 mM ammonium acetate in 0.1% formic acid/water and (B) 0.1% formic acid/acetonitrile.

For basic LCMS data: LCMS were recorded on an Agilent 1200 series LC/MSD or a Shimadzu LCMS 2020 equipped with electrospray ionization and a quadrupole MS detector [ES+ve gives MH ⁺ ] and equipped with an Xbridge C18, 2.1 x 50 mm column packed with 5 mm C18 coated silica or a Kinetex EVOC18 2.1 x 30 mm column packed with 5 mm C18 coated silica, eluting with 0.05 vol% _NH3 - _H2O /water (solvent A) and acetonitrile (solvent B).

HPLC analysis method: HPLC was performed on an X Bridge C18 150×4.6 mm, 5 micron. The column flow rate may be 1.0 ml/min and the mobile phase may include (A) 0.1% ammonia water and (B) 0.1% ammonia/acetonitrile.

Prep HPLC analysis methods: In some cases, compounds were purified on a Shimadzu LC-20AP with UV detector. The column used may include an X-BRIDGE C18 (250×19) mm, 5μ. The column flow rate may be 16.0 ml/min and the mobile phase may include (A) 0.1% formic acid/water and (B) acetonitrile, a basic method using (A) 5 mM ammonium bicarbonate and 0.1% NH3/water and (B) acetonitrile, or (A) 0.1% ammonium hydroxide/water and (B) acetonitrile. UV spectra were recorded at 202 nm and 254 nm.

NMR Methods: 1H NMR spectra were recorded on a Bruker Ultra Shield Advance 400 MHz/5 mm Probe (BBFO) or equivalent. Chemical shifts are reported in parts per million.

As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods depict the synthesis of certain compounds of the present invention, the following general methods and other methods known to those of ordinary skill in the art can be applied to all compounds as described herein and subclasses and species of each of these compounds.

Intermediate

15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4- 1-(4-(4-(4-nitropropenoic acid)-3,6,9,12-tetraoxopentadecanoic acid (Intermediate A1)

This intermediate was synthesized as previously described in WO 2020/113233 and US 2019/192668.

12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4- yl)dodecanoic acid (Intermediate A2)

Step 1 - Dodecan-11-ynoic acid. To a solution of dodecan-11-yn-1-ol (700 mg, 3.84 mmol, CAS# 18202-10-3) in acetone (10 mL) was added Jones reagent (3.7 mL, 9.6 mmol) at 0°C. The mixture was then stirred at 0°C for 2 h. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried _{over Na2SO4} and concentrated under reduced pressure to give the title compound (500 mg, 66%) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.0 (br s, 1H), 2.72 (t, J = 2.6Hz, 1H), 2.22-2.10 (m, 4H), 1.52-1.38 (m, 4H), 1.35-1.33 (m, 2H), 1.28-1.21 (m, 8H).

Step 2 - Benzyl dodecan-11-ynoate. To a solution of dodecan-11-ynoic acid (500 mg, 2.55 mmol) in DMF (10 mL) was added K ₂ CO ₃ (529 mg, 33.8 mmol) and BnBr (523 mg, 3.06 mmol) at 0° C. The mixture was stirred at rt overnight. Upon completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1, v/v) to give the title compound (600 mg, 82%) as a colorless oil. ¹ H NMR: (400MHz, DMSO-d ₆ ) δ7.44-7.25(m,5H),5.08(s,2H),2.72(t,J＝2.6Hz,1H),2.34(t,J＝7.4Hz,2H),2.13(td,J＝6.8,2.8Hz,2H),1.57-1.49(m,2H) ,1.48-1.38(m,2H),1.37-1.29(m,2H),1.25-1.20(m,8H).

Step 3-12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-ynoic acid benzyl ester. Benzyl dodec-11-ynoate (170 mg, 0.6 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (101 mg, 0.3 mmol, intermediate H), Pd(PPh ₃ ) ₂ Cl ₂ (42 mg, 0.06 mmol), CuI (12 mg, 0.06 mmol), Cs ₂ CO ₃ (488 mg, 1.5 mmol) and A mixture of molecular sieves (150 mg) in anhydrous DMF (5 mL) was heated at 85 ° C under microwave irradiation for 40 min. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/2, v/v) to give the title compound (80 mg, 44%) as a yellow solid. LCMS m/z＝544.4[M+H] ⁺ ; ¹ H NMR: (400MHz, DMSO-d ₆ ) δ11.1 (s, 1H), 7.43-7.28 (m, 5H), 7.10 (dd, J＝7.7, 1.3Hz, 1H), 7.04 (dd, J＝7.9, 1.2Hz, 1H), 6.98 (t, J＝7.8 Hz,1H). 5.38(dd,J＝12.8,5.4Hz,1H),5.07(s,2H),3.63(s,3H),2.95-2.81(m,1H),2.77-2.58(m,2H),2.49(t,J＝7.2Hz,2H),2.33(t,J＝7.2Hz,2H),2.05-1.9 8(m,1H),1.60-1.48(m,4H),1.45-1.35(m,2H),1.33-1.21(m,8H).

Step 4-12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecanoic acid. To a solution of benzyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-ynoate (80 mg, 0.15 mmol) in THF (5 mL) was added 10% Pd(OH) ₂ /C (16 mg) and 10% Pd/C (16 mg). The mixture was stirred at 35 °C under H ₂ (1 atm) overnight. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (60 mg, 90%) as a white solid. LCMS m/z=458.4[M+H] ⁺ . ¹ H NMR: (400MHz, DMSO-d ₆ ) δ11.1(s,1H),7.01-6.82(m,3H),5.35(dd,J＝12.6,5.4Hz,1H),3.54(s,3H),2.95-2.82(m,3H),2.76-2.58(m,2H),2.18(t,J＝ 7.3Hz,2H),2.05-1.94(m,1H),1.64-1.53(m,2H),1.53-1.42(m,2H),1.42-1.70(m,14H).

9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4- 4-(4-(2-amino-1-nitrophenyl)nonanoic acid (Intermediate A3)

This intermediate was synthesized as previously described in WO 2020/206424.

2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole (4-oxazol-4-yl)propoxy)ethoxy)acetic acid (Intermediate A4)

Step 1 - tert-Butyl 2-(2-(prop-2-yn-1-yloxy)ethoxy)acetate. To a solution of 2-(prop-2-yn-1-yloxy)ethan-1-ol (500 mg, 4.99 mmol, CAS# 3973-18-0) in anhydrous THF (8 mL) at 0°C under _N2 was added NaH (60% w/w dispersion in oil, 339.6 mg, 8.49 mmol) portionwise and the mixture was stirred at 0°C for 1 h. Subsequently, tert-butyl 2-bromoacetate (974.1 mg, 4.99 mmol) was added and the mixture was stirred at rt overnight. After completion, the reactant was extracted with sat.aq. _NH4Cl solution and the mixture was extracted with EtOAc (20 mL x 4 ₎ . The combined organic phases were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=50/1 to 20/1, v/v) to give the title compound (220 mg, 21%) as a pale yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.21 (d, J=2.4 Hz, 2H), 4.02 (s, 2H), 3.74 (s, 4H), 2.42 (t, J=2.4 Hz, 1H), 1.47 (s, 9H).

Step 2-tert-Butyl 2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)acetate. Tert-butyl 2-(2-(prop-2-yn-1-yloxy)ethoxy)acetate (126.4 mg, 0.59 mmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 0.30 mmol, intermediate H), Pd(PPh ₃ )Cl ₂ (41.4 mg, 0.059 mmol), CuI (11.2 mg, 0.059 mmol), Cs ₂ CO ₃ (479.4 mg, 1.48 g) and A mixture of molecular sieves (150 mg) in anhydrous DMF (8 mL) was heated at 85 ° C under microwave irradiation for 40 min. After completion, the mixture was poured into water and extracted with EtOAc (20 mL×4). The combined organic phase was washed with water, brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/2, v/v) to give the title compound (110 mg, 79%) as a yellow solid. LCMS m/z=470.1[MH] ^- .

Step 3 - tert-Butyl 2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)acetate. To a solution of tert-butyl 2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)acetate (110 mg, 0.23 mmol) in THF (4 mL) was added 10% Pd/C (10 mg) and 10% Pd(OH) ₂ /C (10 mg). The mixture was stirred at 35°C under _H2 (1 atm) overnight. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (90 mg, 81%) as a yellow oil. LCMS m/z = 474.2 [MH] ⁻ .

Step 4 - 2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)acetic acid. To a solution of tert-butyl 2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl- ₂ -oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)propoxy)ethoxy)acetic acid (90 mg) in DCM (3 mL) was added TFA (0.5 mL) and the mixture was stirred at rt under N2 for 6 h. Upon completion, the mixture was concentrated under reduced pressure and the residue was triturated with _Et2O to give the title compound (80 mg, 100%) as a brown solid. LCMS m/z=418.2 [MH] ^- .

15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- 1-(4-(4-(4-nitropropenoic acid)-3,6,9,12-tetraoxopentadecanoic acid (Intermediate B1)

This intermediate was synthesized as previously described in WO 2020/206424, WO 2020/113233 and US 2019/0192668.

12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- 1-(2-amino)dodecanoic acid (Intermediate B2)

Step 1-1 Benzyl 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-ynoate. Benzyl 2-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-ynoate A2-2 (226 mg, 0.79 mmol, synthesized via step 1-2 of intermediate A2), 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (150 mg, 0.44 mmol, intermediate J), Pd(PPh ₃ ) ₂ Cl ₂ (63 mg, 0.09 mmol), CuI (17 mg, 0.09 mmol), Cs ₂ CO ₃ (716 mg, 2.2 mmol) and A mixture of molecular sieves (150 mg) in anhydrous DMF (5 mL) was heated at 85 ° C under microwave irradiation for 40 min. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/2, v/v) to give the title compound (130 mg, 54%) as a yellow solid. LCMS m/z=566.4[M+Na] ⁺ , ¹ H NMR:(400MHz,DMSO-d ₆ )δ11.1(s,1H),7.38-7.28(m,5H),7.21(s,1H),7.08-7.06(m,2H),5.35(dd,J＝12.8,5.4Hz,1H),5.07(s,2H),3.32(s,3H),2.95-2.81(m,1H),2.75- 2.56(m,2H),2.39(t,J＝7.2Hz,2H),2.33(t,J＝7.2Hz,2H),2.03-1.96(m,1H),1.58-1.47(m,4H),1.43-1.34(m,2H),1.32-1.18(m,8H).

Step 2-12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecanoic acid. To a solution of benzyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-ynoate (130 mg, 0.24 mmol) in THF (5 mL) was added 10% Pd(OH) ₂ /C (26 mg) and 10% Pd/C (26 mg). The mixture was stirred at 35 °C under H ₂ (1 atm) overnight. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (100 mg, 92%) as a white solid. LCMS: m/z = 458.4 [M+H] ⁺ .

9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- 4-(4-(2-amino-1-nitrophenyl)nonanoic acid (Intermediate B3)

Step 1 - 3-[5-(9-Hydroxynon-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione. To a solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (12 g, 36 mmol, intermediate J) and non-8-yn-1-ol (14.93 g, 106.5 mmol, CAS# 10160-28-8) in TEA (30.00 mL, 215.8 mmol) and DMSO (60.00 mL, 844.7 mmol) were added CuI (675.83 mg, 3.549 mmol) and Pd(PPh ₃ ) ₄ (4.10 g, 3.55 mmol). After stirring at 85° C. under a nitrogen atmosphere for 3 h, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column: Spherical C18, 20-40 μm, 330 g; mobile phase A: water (plus 10 mM FA); mobile phase B: ACN; flow rate: 80 mL/min; gradient: 5%-5% B, 10 min, 30% B-45% B gradient, in 20 min; detector: 254 nm; elution fraction containing the desired product was collected at 36% B) and concentrated under reduced pressure to give the title compound (9 g, 64% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11(s,1H),7.23(s,1H),7.11-7.07(m,2H),5.38(dd,J＝12.8,5.3Hz,1H),4.35-4.31(m,1H),3.42-3.35(m,2H),3.34(s,3 H),2.92-3.88(m,1H),2.77-2.57(m,2H),2.41(t,J=7.1Hz,2H),2.09-1.98(m,1H),1.57-1.53(m,2H),1.48-1.23(m,8H). LC/MS (ESI, m/z): [(M-1)] ^- = 396.2.

Step 2-3-[5-(9-hydroxynonyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione. To a stirred solution of 3-[5-(9-hydroxynonyl)-1-yn-1-yl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione (9.00 g, 22.6 mmol) in MeOH (1.00 L) was added Pd/C (2.00 g, 1.88 mmol, 10 wt%) at rt. The reaction mixture was purged with hydrogen 3 times and stirred under a hydrogen atmosphere at rt for 3 h. Upon completion, the reaction mixture was filtered through a pad of celite and concentrated under reduced pressure to give the title compound (9 g, 99% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 7.02-6.99 (m, 2H), 6.86 (d, J = 8.0Hz, 1H), 5.34 (dd, J = 12.7, 5.4Hz, 1H), 4.35-4.30 (m, 1H), 3.39-3.35 (m, 2H), 3. 32(s,3H),2.95-2.84(m,1H),2.73-2.58(m,4H),2.02-1.98(m,1H),1.62-1.57(m,2H),1.39-1.27(m,12H). LC/MS (ESI, m/z): [(M+1)] ⁺ =402.3.

Step 3 - 9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)nonanoic acid. To a solution of 3-(5-(9-hydroxynonyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 249 μmol) in MeCN/H ₂ O (10/1, 5.0 mL) was added PIDA (401 mg, 1.25 mmol) and TEMPO (7.78 mg, 49.8 μmol) and the mixture was stirred at rt overnight. After completion, the reaction mixture was poured into water and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15/1, v/v) to give the title compound (92 mg, 89%) as a pink solid. LCMS: m/z=416.2 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.0 (br s, 1H), 11.1 (s, 1H), 6.97-6.93 (m, 2H), 6.87-6.83 (m, 1H), 5.37 (dd, J = 12.5, 5.4Hz, 1H), 3.54 (s, 3H), 2.92-2.83 (m, 3H ),2.75-2.57(m,2H),2.18(t,J＝7.4Hz,2H),2.04-1.92(m,1H),1.63-1.53(m,2H),1.53-1.43(m,2H),1.41-1.21(m,8H).

2-(2-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole (4-(2-oxazol-5-yl)propoxy)ethoxy)acetic acid (Intermediate B4)

This intermediate was synthesized as previously described in WO 2020/206424 and US 2019/192668.

14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)-3,6,9,12- Tetraoxatetradecanoic acid (Intermediate C1)

This intermediate was synthesized as previously described in WO 2020/113233 and US 2019/192668.

12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecanoic acid (intermediate C2)

To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.87 g, 8.7 mmol, CAS#835616-60-9) in NMP (20 mL) was added 12-aminododecanoic acid (2.0 g, 7.2 mmol, CAS#693-57-2) and DIEA (1.87 g, 14.5 mmol). The mixture was heated at 90 °C overnight. Upon completion, the reaction mixture was cooled to rt and directly purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 40/60, v/v, 0.1% HCOOH) to give the title compound (1.4 g, 41%) as a yellow solid. LCMS: m/z=472.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.2 (br s,1H),11.1(s,1H),7.57(dd,J＝8.4,7.2Hz,1H),7.08(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.51(t,J＝5.8Hz,1H),5.04(dd,J＝12.9,5.4Hz,1H),3.31- 3.23(m,3H),2.95-2.82(m,1H),2.63-2.53(m,1H),2.17(t,J=7.4Hz,2H),2.10-1.96(m,1H),1.65-1.41(m,4H),1.41-1.20(m,14H).

8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octanoic acid (Intermediate C3)

To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.00 g, 3.62 mmol, CAS#835616-60-9) in NMP (18 mL) was added 8-aminooctanoic acid (0.69 g, 4.34 mmol, CAS#1002-57-9) and DIEA (1.40 g, 10.9 mmol). The mixture was heated at 90 °C overnight. Upon completion, the reaction mixture was cooled to rt, diluted with water (100 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried _{over Na2SO4} and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/ _H2O , 40/60, v/v, 0.1% HCOOH) to give the title compound (0.8 g, 53%) as a light green solid. LCMS: m/z＝416.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ11.1(s,1H),7.57(dd,J＝8.5,7.1Hz,1H),7.08(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.51(t,J＝5.8Hz,1H),5.04(dd,J＝12.8,5.4Hz,1H),3.31-3.23(m ,3H),2.95-2.81(m,1H),2.64-2.50(m,1H),2.18(t,J=7.2Hz,2H),2.08-1.95(m,1H),1.62-1.40(m,4H),1.37-1.08(m,6H).

2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy (4-(2-(4-(2-ethoxy)acetic acid) (Intermediate C4)

This intermediate was synthesized as previously described in US 2019/0192668.

3-(4-(1-amino-3,6,9,12-tetraoxapentadeca-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene (d]imidazol-1-yl)piperidin-2,6-dione (Intermediate D1)

This intermediate was synthesized as previously described in US20190192668.

3-(4-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin- 2,6-Diketone (Intermediate D2)

Step 1 - 4-methylbenzenesulfonic acid dodecan-11-yn-1-yl ester. To a solution of dodecan-11-yn-1-ol (200 mg, 517 μmol, CAS# 18202-10-3) and TsCl (416 mg, 2.19 mmol) in DCM (5 mL) was added TEA (333 mg, 3.29 mmol) and DMAP (13.4 mg, 110 μmol). The mixture was stirred at rt under _N2 for 2 h. After completion, the reaction was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=50/1, v/v) to give the title compound (200 mg, 54%) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.79(d,J＝8.4Hz,2H),7.34(d,J＝8.4Hz,2H),4.01(t,J＝6.5Hz,2H),2.45(s,3H),2.17(td,J＝7.1,2.6Hz,2H),1.93(t,J＝2.6Hz,1H ),1.68-1.57(m,2H),1.55-1.46(m,2H),1.42-1.32(m,2H),1.31-1.18(m,10H).

Step 2-12-Azidododec-1-yne. To a solution of 4-methylbenzenesulfonic acid dodecan-11-yn-1-yl ester (2.4 g, 7.1 mmol) in DMF (40 mL) was added NaN ₃ (696 mg, 10.7 mmol) and the mixture was heated at 45° C. overnight. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (1.2 g, 81%) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ3.25 (t, J = 7.0 Hz, 2H), 2.18 (td, J = 7.2, 2.6 Hz, 2H), 1.94 (t, J = 2.6 Hz, 1H), 1.65-1.47 (m, 6H), 1.44-1.23 (m, 10H).

Step 3 - Dodecan-11-yn-1-amine. To a solution of 12-azidododec-1-yne (1.2 g, 5.79 mmol) in THF (30 mL) was added _PPh3 (1.82 g, 6.95 mmol) and _H2O (104 mg, 5.79 mmol) and the mixture was stirred at rt overnight. After completion, the reaction was concentrated under reduced pressure and the residue was triturated with petroleum ether and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.0 g, 96%) as a colorless oil.

Step 4 - tert-Butyl dodecan-11-yn-1-ylcarbamate. To a solution of dodecan-11-yn-1-amine (1.0 g, 5.52 mmol) in DCM (30 mL) was added _Boc2O (1.44 g, 6.62 mmol) and TEA (1.11 g, 11.1 mmol) and the mixture was stirred at rt overnight. After completion, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=30/1, v/v) to give the title compound (1.2 g, 77%) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.74 (t, J = 5.2 Hz, 1H), 2.92-2.84 (m, 2H), 2.71 (t, J = 2.6 Hz, 1H), 2.13 (td, J = 6.8, 2.6 Hz, 2H), 1.45-1.29 (m, 16H), 1.23 (s, 9H).

Step 5: tert-Butyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)carbamate. tert-Butyl dodec-11-yn-1-ylcarbamate (249 mg, 887 μmol), 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (150 mg, 443 μmol, intermediate H), Pd(PPh ₃ ) ₂ Cl ₂ (32.3 g, 88.7 μmol), CuI (16.8 mg, 88.7 μmol), Cs ₂ CO ₃ (719 mg, 2.21 mmol) and A mixture of molecular sieves (200 mg) in anhydrous DMF (8.0 mL) was heated at 85 ° C under microwave irradiation for 1 h. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15/1, v/v) to give the title compound (90 mg, 38%) as a colorless oil. LCMS m/z=539.3[M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.1(s,1H),7.10(dd,J＝7.7,1.3Hz,1H),7.07-7.02(m,1H),6.98(t,J＝7.8Hz,1H),6.72(t,J＝5.6Hz,1H),5.37(dd,J＝12.8,5.2Hz,1H),3.63(s,3H),2 .91-2.84(m,3H),2.73-2.59(m,2H),2.47(t,J＝7.2Hz,2H),2.05-1.98(m,1H),1.61-1.53(m,2H),1.46-1.39(m,2H),1.36-1.26(m,12H),1.24(s,9H ).

Step 6-tert-Butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecyl)carbamate. To a solution of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)carbamate (249 mg, 887 μmol) in THF (10.0 mL) was added 10% Pd/C (20 mg) and 10% Pd(OH) ₂ /C (20 mg). The mixture was stirred at 35 °C under _H2 (1 atm) for 20 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (60 mg, 66%) as a white solid. LCMS m/z＝543.3[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.24 (br s, 1H), 6.97 (t, J＝7.6Hz, 1H), 6.88 (d, J＝7.7Hz, 1H), 6.65 (d, J＝7.8Hz, 1H), 5.20 (dd, J＝12.3, 5.4Hz, 1H),3.66(s,3H),3.16-3.04(m,2H),2.93-2.83(m,3H),2.32-2.16(m,2H),2.08-1.82(m,3H),1.66-1.59(m,4H),1.51-1.24(m,23H).

Step 7 - 3-(4-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride. A mixture of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodecyl)carbamate (60 mg, 110 μmol) and 4M HCl in dioxane (10.0 mL) was stirred at rt for 3 h. Upon completion, the mixture was concentrated under reduced pressure to give the title compound (50 mg, 96%) as a white solid. LCMS m/z=443.2 [M+H] ⁺ .

3-(4-(9-aminononyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2, 6-Diketone (Intermediate D3)

Step 1 - tert-Butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]non-8-yn-1-yl]carbamate. To a stirred mixture of 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate H) and tert-butyl N-(non-8-yn-1-yl)carbamate (8.49 g, 35.5 mmol, intermediate O) in DMA (40.0 mL) and TEA (20.0 mL) was added Pd(PPh ₃ ) ₄ (2.73 g, 2.37 mmol) portionwise at rt under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. After completion, the resulting mixture was diluted with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse phase flash (column: Spherical C18, 20 to 40 μm, 330 g; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient (B%): 5% to 5%, 8 min; 40% to 60%, 30 min; 60% to 95%; 0 min; 95%, 5 min; detector: 254 nm; Rt: 23.4 min.) to give the title compound (6.4 g, 55% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12 (s, 1H), 7.11 (dd, J = 7.8, 1.3Hz, 1H), 7.05 (dd, J = 7.9, 1.2Hz, 1H), 6.99 (t, J = 7.8Hz, 1H), 6.77 (t, J = 5.8Hz, 1H), 5.39 (dd, J = 12. 7,5.4Hz,1H),3.64(s,3H),2.98-2.78(m,3H),2.74-2.59(m,2H),2.52-2.46(m,2H),2.06-1.96(m,1H),1.61-1.54(m,2H),1.45-1.34(m,13H),1. 33-1.19(m,4H). LC/MS (ESI, m/z): [(M+1)] ⁺ =497.3.

Step 2 - tert-Butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]nonyl]carbamate. To a stirred mixture of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]non-8-yn-1-yl]carbamate (6.40 g, 12.9 mmol) in MeOH (500 mL) was added portionwise Pd/C (1371.48 mg, 12.887 mmol) at rt under a nitrogen atmosphere. The resulting mixture was stirred at rt under a hydrogen atmosphere for 4 h. Upon completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3×100 mL). The filtrate was concentrated under reduced pressure to give the title compound (6.0 g) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.02-6.91 (m, 2H), 6.88-6.85 (m, 1H), 6.75 (t, J = 5.7Hz, 1H), 5.37 (dd, J = 12.6, 5.4Hz, 1H), 3.55 (s, 3H), 2.90-2. 87(m,3H),2.78-2.56(m,2H),2.04-1.94(m,1H),1.61-1.56(m,2H),1.38-1.32(m,15H),1.29-1.19(m,8H). LC/MS (ESI, m/z): [(M+1)] ⁺ =501.3.

Step 3 - 3-[4-(9-aminononyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]nonyl]carbamate (6.00 g, 12 mmol) in DCM (20.0 mL) was added HCl (4M) in 1,4-dioxane (20.0 mL) at rt under nitrogen atmosphere, and the solution was stirred at rt for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (3.9 g, 91% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11 (s, 1H), 8.03 (broad peak, 3H), 7.03-6.91 (m, 2H), 6.89-6.86 (m, 1H), 5.40 (dd, J = 12.6, 5.4Hz, 1H), 3.57 (s, 3H), 2.94-2.85 (m, 3 H),2.81-2.57(m,4H),2.03-1.97(m,1H),1.64-1.53(m,4H),1.41-1.26(m,10H). LC/MS(ESI,m/z):[(M+1)] ⁺ =401.3.

3-(4-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]Imidazol-1-yl)piperidine-2,6-dione (Intermediate D4)

This intermediate was synthesized as previously described in WO 2020/113233 and US 2019/192668.

3-(4-(6-aminohexyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6- Diketone (Intermediate D5)

Step 1 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hex-5-yn-1-yl]carbamate. To a stirred mixture of 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate H) and tert-butyl N-(hex-5-yn-1-yl)carbamate (7.00 g, 35.5 mmol) in DMA (40.00 mL) and TEA (20.00 mL) was added Pd(PPh ₃ ) ₄ (2.73 g, 2.37 mmol) portionwise at rt under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. After completion, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3×75 mL). The combined organic layers were washed with brine (3×50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse phase rapid under the following conditions (column: Spherical C18, 20 to 40 μm, 330 g; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient (B%): 5% to 5%, 8 min; 40% to 60%, 30 min; 60% to 95%; 0 min; 95%, 5 min; detector: 254 nm; Rt: 23.4 min.) to give the title compound (4.5 g, 42% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12 (s, 1H), 7.12 (d, J = 7.7Hz, 1H), 7.06 (dd, J = 7.9, 1.2Hz, 1H), 6.99 (t, J = 7.8Hz, 1H), 6.85 (t, J = 5.7Hz, 1H), 5.39 (dd, J = 12.7, 5. 3Hz,1H),3.64(s,3H),2.99-2.93(m,2H),2.92-2.84(m,1H),2.81-2.59(m,2H),2.52-2.47(m,2H),2.05-1.99(m,1H),1.57-1.51(m,4H),1.38(s,9H ). LC/MS (ESI, m/z): [(M+1)] ⁺ =455.3.

Step 2 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hexyl]carbamate. To a stirred mixture of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hex-5-yn-1-yl]carbamate (5.50 g, 12.1 mmol) in MeOH (500.00 mL) was added Pd/C (1.29 g, 12.1 mmol) portionwise at rt under a nitrogen atmosphere. The resulting mixture was stirred at rt under a hydrogen atmosphere for 4 h. After completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3×100 mL). The filtrate was concentrated under reduced pressure to give the title compound (5 g, 90% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 6.99-6.92 (m, 2H), 6.86 (dd, J = 5.5, 3.5Hz, 1H), 6.77 (t, J = 5.6Hz, 1H), 5.37 (dd, J = 12.6, 5.4Hz, 1H), 3.55 (s, 3H), 2.92-2.85(m,5H),2.79-2.56(m,2H),2.03-1.99(m,1H),1.61-1.56(m,2H),1.37(s,13H),1.34-1.29(m,2H). LC/MS(ESI,m/z):[(M+1)] ⁺ =459.3.

Step 3-3-[4-(6-aminohexyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hexyl]carbamate (5.00 g, 10.9 mmol) in DCM (20.0 mL) was added a 1,4-dioxane solution (20.0 mL) of HCl (4 M). The solution was stirred at rt for 4 h. After completion, the reaction mixture was concentrated under reduced pressure to give the title compound (3.9 g, 91% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.11 (s, 1H), 8.04 (broad peak, 3H), 7.08-6.91 (m, 2H), 6.90-6.86 (m, 1H), 5.40 (dd, J = 12.6, 5.4Hz, 1H), 3.57 (s, 3H), 2.98-2.84 (m, 3H),2.80-2.73(m,2H),2.71-2.57(m,2H),2.04-1.98(m,1H),1.63-1.56(m,4H),1.49-1.32(m,4H). LC/MS(ESI,m/z):[(M+1)] ⁺ =359.3.

3-(5-(1-amino-3,6,9,12-tetraoxapentadeca-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene (d)imidazol-1-yl)piperidine-2,6-dione (Intermediate E1)

A mixture of tert-butyl (15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-3,6,9,12-tetraoxapentadecyl)carbamate (50 mg, 84 μmol, synthesized as described in WO2019060693) and 4M HCl in dioxane (10.0 mL) was stirred at rt for 3 h. Upon completion, the mixture was concentrated under reduced pressure to give the title compound as a yellow solid (60 mg, >100%). LCMS m/z=493.4[M+H] ⁺ .

3-(5-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin- 2,6-Diketone (Intermediate E2)

Step 1-tert-Butyl 12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-yn-1-yl)carbamate. 3-(5-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (100 mg, 295 μmol, Intermediate J), tert-butyl dodec-11-yn-1-ylcarbamate (141 mg, 502 μmol, synthesized via steps 1-4 of Intermediate D2), Pd(PPh ₃ ) ₂ Cl ₂ (41.5 mg, 59 μmol), CuI (11.2 mg, 59 μmol), Cs ₂ CO ₃ (479 mg, 1.4 mmol) and A mixture of molecular sieves (200 mg) in anhydrous DMF (8.0 mL) was heated at 85 ° C under microwave irradiation for 1 h. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=15/1, v/v) to give the title compound (65 mg, 41%) as a colorless oil. LCMS m/z＝539.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.1 (s, 1H), 7.22 (s, 1H), 7.10-7.05 (m, 2H), 6.73 (t, J = 5.2Hz, 1H), 5.36 (dd, J = 12.8, 5.4Hz, 1H), 3.34 ( s,3H),2.92-2.84(m,3H),2.74-2.59(m,2H),2.40(t,J=7.0Hz,2H),2.07-1.97(m,1H),1.58-1.49(m,2H),1.45-1.19(m,23H).

Step 2-tert-Butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecyl)carbamate. To a solution of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodec-11-yn-1-yl)carbamate (100 mg, 185 μmol) in THF (10.0 mL) was added 10% Pd/C (20 mg) and 10% Pd(OH) ₂ /C (20 mg). The mixture was stirred at 35 °C under _H2 (1 atm) for 20 h. Upon completion, the reaction was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (60 mg, 59%) as a white solid. LCMS m/z＝543.2[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.13 (br s, 1H), 6.88 (dd, J＝8.1, 1.5Hz, 1H), 6.84 (d, J＝1.4Hz, 1H), 6.70 (d, J＝8.0Hz, 1H), 5.20 (dd, J＝12.5, 5 .3Hz,1H),3.42(s,3H),3.15-3.01(m,2H),2.99-2.68(m,3H),2.67-2.60(m,2H),2.29-2.18(m,1H),1.64-1.59(m,2H),1.44(s,12H),1.36-1.23(m, 15H).

Step 3 - 3-(5-(12-aminododecyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride. A mixture of tert-butyl (12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)dodecyl)carbamate (60 mg, 110 μmol) and 4M HCl in dioxane (10.0 mL) was stirred at rt for 3 h. Upon completion, the mixture was concentrated under reduced pressure to give the title compound as a yellow solid (60 mg, >100%). LCMS m/z = 443.3 [M+H] ⁺ .

3-(5-(9-aminononyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2, 6-Diketone (Intermediate E3)

Step 1 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-yn-1-yl]carbamate. To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, Intermediate J) and tert-butyl non-8-yn-1-ylcarbamate (9.33 g, 47.3 mmol, Intermediate O) in DMSO (40.00 mL) and TEA (20.00 mL) were added Pd( _PPh3 ) ₄ (2.73 g, 2.37 mmol) and CuI (450.55 mg, 2.366 mmol) portionwise at rt under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 3h. After completion, the reaction mixture was diluted with EtOAc (800mL). The resulting mixture was washed with 4×400mL water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (1: 2) to give the title compound (7.2g, 67% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09 (s, 1H), 7.23-7.21 (m, 1H), 7.10-7.06 (m, 2H), 6.75-6.72 (m, 1H), 5.36 (dd, J = 12.8, 5.3Hz, 1H), 3.30 (s, 3H), 2.92-2.83 (m,3H),2.75-2.55(m,2H),2.40(t,J＝7.0Hz,2H),2.06-1.98(m,1H),1.57-1.50(m,2H),1.43-1.34(m,13H),1.31-1.23(m,4H). LC/MS(ESI,m/z):[(M+1-56)] ⁺ =497.3.

Step 2 - tert-Butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]nonyl]carbamate. To a stirred solution of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]non-8-yn-1-yl]carbamate (7.00 g, 14.1 mmol) in MeOH (500.0 mL) was added portionwise Pd/C (2.00 g, 1.88 mmol, 10 wt%) at rt under a nitrogen atmosphere. The resulting mixture was stirred at rt under a hydrogen atmosphere for 24 h. After completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, ACN/water, gradient 60% to 80% in 25 min; detector, UV 254 nm) to give the title compound (7 g) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 7.05-6.96 (m, 2H), 6.87-6.84 (m, 1H), 6.78-6.69 (m, 1H), 5.34 (dd, J = 12.7, 5.4Hz, 1H), 3.32 (s, 3H), 2.92-2.8 7(m,3H),2.77-2.63(m,2H),2.62-2.58(m,2H),2.05-1.95(m,1H),1.61-1.55(m,2H),1.39-1.34(s,11H),1.31-1.20(m,10H). LC/MS(ESI,m/z):[(M+1-56)] ⁺ =501.3.

Step 3 - 3-[5-(9-aminononyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[9-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]nonyl]carbamate (6.00 g, 12.0 mmol) in DCM (15.00 mL) was added dropwise 4M HCl(gas) in 1,4-dioxane (15.00 mL) at rt under nitrogen atmosphere. The resulting mixture was stirred at rt under nitrogen atmosphere for 4 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with _Et2O to give the title compound (5 g, 96% yield) as an off-white solid. ¹ H NMR (400MHz, methanol-d ₄ ) δ7.06-7.00(m,2H),6.97-6.94(m,1H),5.33(dd,J＝12.3,5.4Hz,1H),3.43(s,3H),2.98-2.87(m,3H),2.86-2.75(m,2H),2.70 (t,J＝7.6Hz,2H),2.21-2.15(m,1H),1.75-1.59(m,4H),1.45-1.30(m,10H). LC/MS (ESI, m/z): [(M+1-56)] ⁺ =401.3.

3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]Imidazol-1-yl)piperidine-2,6-dione (Intermediate E4)

This intermediate was synthesized as previously described in US 2019/192668 and WO 2020/010210.

3-(5-(6-aminohexyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6- Diketone (Intermediate E5)

Step 1 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-yn-1-yl]carbamate. To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, Intermediate J) and tert-butyl N-(hex-5-yn-1-yl)carbamate (9.33 g, 47.3 mmol, CAS# 151978-58-4) in DMSO (40.0 mL) and TEA (20.0 mL) was added Pd(PPh ₃ ) ₄ portionwise at rt under nitrogen atmosphere. (2.73 g, 2.37 mmol) and CuI (450.55 mg, 2.366 mmol). The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 3 h. After completion, the reaction mixture was diluted with EtOAc (800 mL) and washed with 4×400 mL of water. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:2) to give the title compound (7.2 g, 67% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 7.24 (d, J = 1.2Hz, 1H), 7.09 (d, J = 1.2Hz, 2H), 6.83 (t, J = 5.7Hz, 1H), 5.38 (dd, J = 12.7, 5.4Hz, 1H), 3.34 (s, 3H), 2.97 (d,J＝5.1Hz,2H),2.91-2.83(m,1H),2.77-2.57(m,2H),2.44-2.37(m,2H),2.06-2.00(m,1H),1.56-1.50(m,4H),1.38(s,9H); LC/MS(ESI,m/z):[(M+1) ] ⁺ =355.3.

Step 2 - tert-Butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hexyl]carbamate. To a stirred solution of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hex-5-yn-1-yl]carbamate (6.00 g, 13.2 mmol) in MeOH (500 mL) was added portionwise Pd/C (1.97 g, 1.85 mmol, 10 wt%) at rt under a nitrogen atmosphere. The resulting mixture was stirred at rt under a hydrogen atmosphere for 48 h. After completion, the reaction mixture was filtered and the filter cake was washed with MeOH (3×100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, ACN/water, gradient 60% to 80% in 25 min; detector, UV 254 nm) to give the title compound (5 g, 83%) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ11.07(s,1H),7.05-6.96(m,2H),6.86(m,1H),6.76-6.73(m,1H),5.36-5.31(m,1H),3.18(d,J＝5.2Hz,1H),2.92-2.86(m,3H ),2.72(m,1H),2.67-2.62(m,1H),2.62-2.57(m,2H),2.03-1.98(m,1H),1.57(d,J＝7.5Hz,2H),1.39-1.34(m,13H),1.32-1.25(m,4H). LC/MS (ESI, m/z): [(M+1)] ⁺ =359.2.

Step 3 - 3-[5-(6-aminohexyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[6-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hexyl]carbamate (4.8 g) in DCM (20 mL) was added dropwise 4M HCl(g) in 1,4-dioxane (20 mL) at rt under nitrogen atmosphere. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with _Et2O to give the title compound (4 g, 97% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08 (s, 1H), 8.01 (broad peak, 3H), 7.07-6.97 (m, 2H), 6.88-6.85 (m, 1H), 5.36 (dd, J = 12.7, 5.4Hz, 1H), 3.50-3.36 (m, 2H), 3.32 (s, 3H),3.00-2.82(m,1H),2.77-2.71(m,2H),2.66-2.60(m 2H),2.05-1.94(m,1H),1.62-1.51(m,4H),1.42-1.18(m,4H).

4-((12-aminododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate F2)

Step 1-tert-Butyl (12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)carbamate. To a solution of tert-butyl (12-aminododecyl)carbamate (900 mg, 333 μmol, CAS# 109792-60-1) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (993 mg, 399 μmol, CAS# 835616-60-9) in DMF (15.0 mL) was added DIPEA (774 mg, 666 μmol) and the mixture was kept at 90 °C under _N2 overnight. After completion, the mixture was poured into water and extracted with DCM (10 mL x 3). The combined organic _phase was dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 60/40, v/v, 0.1% HCOOH) to give the title compound (586 mg, 54%) as a yellow-green semisolid. LCMS m/z=557.3 [M+H] ⁺ . 1H NMR (400 MHz, CDCl ₃ ) δ8.20 (br s, 1H), 7.48 (dd, J=8.5, 7.1 Hz, 1H), 7.08 (d, J=7.1 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.22 (t, J=5.6 Hz, 1H), 4.91 (dd, J=12.1, 5.3 Hz, 1H), 4.51 (br s, 1H), 3.89 (d, J=3.8 Hz, 1H), 4.60 (t, J=13.3 Hz, 1H), 3.98 (d, J=13.7 Hz, 1H), 3.50 (br s,1H),3.27-3.23(m,2H),3.15-3.03(m,2H),2.92-2.67(m,3H),2.18-2.08(m,1H),1.69-1.65(m,2H),1.44(s,12H),1.33-1.23(m,15H).

Step 2 - 4-((12-aminododecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (12-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)dodecyl)carbamate (140 mg, 252 μmol) and 4M HCl in dioxane (14.0 mL) was stirred at rt for 2 h. After completion, the mixture was concentrated under reduced pressure to give the title compound (118 mg, 96%) as a yellow oil. LCMS m/z = 457.3 [M+H] ⁺ .

4-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole Indole-1,3-dione (Intermediate F3)

This intermediate was synthesized as previously described in US 2019/192668.

4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate F4)

Step 1-tert-Butyl(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate. To a solution of tert-butyl(8-aminooctyl)carbamate (450 mg, 1.85 mmol, CAS#88829-82-7) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (612 mg, 2.21 mmol, CAS#835616-60-9) in DMF (8 mL) was added DIPEA (476.9 mg, 3.69 mmol) and the mixture was heated at 90 °C under _N2 overnight. Upon completion, the mixture was diluted with water (80 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried _{over Na2SO4} and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 40/60, v/v, 0.1% HCOOH) to give the title compound (350 mg, 38% yield) as a green solid. LCMS: m/z=501.25 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.1 (s, 1H), 7.60-7.55 (m, 1H), 7.08 (d, J = 8.6Hz, 1H), 7.01 (d, J = 7.0Hz, 1H), 6.74 (t, J = 5.2Hz, 1H), 6.52 (t, J = 6.0Hz, 1H), 5.0 5(dd,J＝12.8,5.4Hz,1H),3.30-3.26(m,2H),2.97-2.79(m,4H),2.63-2.52(m,2H),1.41-1.27(m,21H).

Step 2 - 4-((8-aminooctyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)octyl)carbamate (350 mg, 0.70 mmol) and 4M HCl in dioxane (8 mL) was stirred at rt for 1 h. After completion, the mixture was concentrated under reduced pressure to give the title compound as a green solid (300 mg, 98% yield). LCMS: m/z = 401.20 [M+H] ⁺ .

4-((9-aminononyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (Intermediate F5 )

Step 1 - tert-Butyl N-(9-hydroxynonyl)carbamate. To a stirred solution of 9-aminononan-1-ol hydrochloride (42.00 g, 214.6 mmol) and TEA (59.5 mL, 429 mmol) in DCM (500.00 mL) at 0°C was added Boc ₂ O (56.20 g, 257.5 mmol) portionwise. The resulting mixture was stirred overnight at rt under nitrogen atmosphere. Upon completion, the resulting mixture was diluted with water (300 mL) and the aqueous layer was extracted with CH ₂ Cl ₂ (300 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:1) to give the title compound (53 g, 95% yield) as a colorless oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.58 (broad peak, 1H), 3.64-3.56 (m, 2H), 3.07 (t, J=6.9 Hz, 2H), 1.54 (p, J=7.6, 6.2 Hz, 2H), 1.46 (s, 9H), 1.34-1.24 (m, 12H); LC/MS (ESI, m/z): [(M-1)] ⁺ ＝258.3.

Step 2 - tert-Butyl N-[9-(methylsulfonyloxy)nonyl]carbamate. To a stirred solution of tert-butyl N-(9-hydroxynonyl)carbamate (50.00 g, 192.8 mmol) and TEA (54.54 mL, 385.5 mmol) in DCM (1.00 L) was added MsCl (33.12 g, 289.1 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting solution was stirred for 3 h at rt under nitrogen atmosphere. After completion, the resulting solution was diluted with water (500 mL) and _the aqueous layer was extracted with _CH2Cl2 (200 mL x ₃ ). The combined organic layers were dried over anhydrous _Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (66 g) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.52 (broad peak, 1H), 4.24 (t, J=6.6 Hz, 2H), 3.17-3.05 (m, 2H), 3.02 (s, 3H), 1.82-1.69 (m, 2H), 1.53-1.39 (m, 14H), 1.33-1.24 (m, 8H); LC/MS (ESI, m/z): [(M-1)] ⁺ ＝336.1.

Step 3 - tert-Butyl N-(9-azidononyl)carbamate. A mixture of tert-butyl N-[9-(methylsulfonyloxy)nonyl]carbamate (66.00 g, 195.6 mmol) and NaN ₃ (22.88 g, 352.0 mmol) in DMF (400.0 mL) was stirred at 40° C. under nitrogen atmosphere for 4 h. Upon completion, the resulting mixture was cooled to rt and diluted with water (800 mL). The resulting mixture was extracted with co-solvent (PE:EA=2:1) (2×1.5 L). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (5:1) to give the title compound (50.8 g, 91% yield) as a light yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.71(t,J＝5.6Hz,1H),3.31(t,J＝6.9Hz,2H),2.90(q,J＝6.6Hz,2H),1.53(p,J＝6.9Hz,2H),1.40-1.36(m,11H),1.29-1.24(m,10H ).

Step 4 - tert-Butyl N-(9-aminononyl)carbamate. A solution of tert-butyl N-(9-azidononyl)carbamate (47.00 g, 165.3 mmol) and _PPh3 (47.68 g, 181.8 mmol) in THF (500.00 mL) and _H2O (50.00 mL) was stirred under nitrogen atmosphere at 55°C overnight. Upon completion, the solution was cooled to rt and concentrated under reduced pressure to give the title compound (100 g) as a white solid.

Step 5 - tert-Butyl N-(9-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]nonyl)carbamate. To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (481.03 mg, 1.741 mmol, CAS# 835616-60-9) and tert-butyl N-(9-aminononyl)carbamate (450.00 mg, 1.741 mmol) in DMA (8.00 mL) was added DIEA (450.14 mg, 3.483 mmol) dropwise. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 h. Upon completion, the mixture was cooled to rt. The resulting mixture was diluted with water (800 mL) and extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (2:1) to give the title compound (50 g, 18% yield) as a green solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 7.55-7.52 (m, 1H), 7.09 (d, J = 8.6Hz, 1H), 7.02 (d, J = 7.0Hz, 1H), 6.75 (t, J = 5.7Hz, 1H), 6.52 (t, J = 5.9Hz, 1H), 5.06 (dd,J＝12.9,5.4Hz,1H),3.29(q,J＝6.7Hz,2H),2.93-2.87(m,3H),2.68-2.53(m,2H),2.14-2.01(m,1H),1.61-1.54(m,2H),1.38-1.24(m,21H). LC/MS (ESI, m/z): [(M+1)] ⁺ =515.4.

Step 6 - 4-[(9-aminononyl)amino]-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride. To a stirred solution of tert-butyl N-(9-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]nonyl)carbamate (57.00 g, 111 mmol) in DCM (150 mL) was added dropwise 4M HCl(g) in 1,4-dioxane (150 mL) at rt under nitrogen atmosphere. The resulting mixture was stirred overnight at rt under nitrogen atmosphere. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (400 mL) and stirred overnight at rt under nitrogen atmosphere. The precipitated solid was collected by filtration and dried in vacuo to give the title compound (13 g, 26% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.94 (broad peak, 3H), 7.61-7.57 (m, 1H), 7.10 (d, J = 8.6Hz, 1H), 7.03 (d, J = 7.0Hz, 1H), 6.53 (t, J = 5.9Hz, 1H), 5.06 (dd, J ＝12.8,5.4Hz,1H),3.30(q,J＝6.6Hz,2H),2 .92-2.88(m,1H),2.75(q,J＝7.3,6.8Hz,2H),2.62(t,J＝3.6Hz,1H),2.59-2.56(m,1H),2.10-1.97(m,1H),1.59-1.55(m,4H),1.39-1.24(m,11H); LC /MS(ESI,m/z):[(M+1)] ⁺ =415.2.

4-((5-aminopentyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (intermediate F6)

This intermediate was synthesized as previously described in US 2019/192668.

4-((6-((4-aminopiperidin-1-yl)sulfonyl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindole Indole-1,3-dione (Intermediate G1)

Step 1 - S-(6-(1,3-dioxoisoindolin-2-yl)hexyl)thioacetate. To a solution of 2-(6-bromohexyl)isoindoline-1,3-dione (3.0 g, 9.68 mmol, CAS# 24566-79-8) in DMF (90 mL) was added KSAc (3.31 g, 29.04 mmol) and the mixture was stirred at rt under N2 for ₂ h. After completion, the mixture was diluted with water (50 mL ₎ and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (2.3 g, 75% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.86-7.80(m,2H),7.73-7.67(m,2H),3.67(t,J＝7.2Hz,2H),2.85(t,J＝7.3Hz,2H),2.30(s,3H),1.73-1.65(m,2H),1.58-1.51 (m,2H),1.38(m,4H).

Step 2 - 6-(1,3-dioxoisoindolin-2-yl)hexane-1-sulfonyl chloride. To a solution of S-(6-(1,3-dioxoisoindolin-2-yl)hexyl)thioacetate (1.0 g, 3.28 mmol) and 2M aqueous HCl (2 mL) in MeCN (25.0 mL) was added NCS (1.18 g, 8.81 mmol) portionwise at 0°C and the mixture was allowed to warm to rt and stirred for 1 h. Upon completion, the mixture was diluted with ice-cold water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (1.1 g, 80% yield) as an off-white solid. LCMS: m/z=330.2 [M+H] ⁺ .

Step 3-tert-Butyl(l-((6-(l,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of 6-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride (1.1 g, 3.34 mmol) and tert-butylpiperidin-4-ylcarbamate (668 mg, 3.34 mmol, CAS#73874-95-0) in DCM (20.0 mL) was added TEA (675 mg, 6.67 mmol) and the mixture was stirred at rt overnight. After completion, the solid was collected by filtration to give the title compound (630 mg, 38% yield) as a white solid. The filtrate was diluted with water (30 mL), extracted with DCM (50 mL x 3) and _the combined organic layers were dried over _Na2S04 and concentrated under reduced pressure. The residue was purified by C18 reverse phase chromatography (Biotage, MeCN/ _H2O , 65/35, v/v, 0.1% HCOOH) to give another aliquot of the title compound as a white solid (500 mg, 30% yield). LCMS: m/z = 494.2 [M+H] ⁺ ; ^1H NMR (400 MHz, _CDCl3 ) δ 7.87-7.82 (m, 2H), 7.74-7.69 (m, 2H), 4.58 (br s, 1H), 3.77-3.63 (m, 4H), 3.58 (br s, 1H), 2.94-2.83 (m, 4H), 2.08-1.95 (m, 2H), 1.83-1.66 (m, 4H), 1.53-1.32 (m 15H).

Step 4-tert-butyl (1-((6-aminohexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((6-(1,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl) _carbamate (900 mg, 1.82 mmol) in DCM/EtOH ( _2/1 , 54.0 mL) was added _N2H4.H2O (98%, 365 mg, 7.29 mmol) and the mixture was heated at 50 °C overnight. After completion, the mixture was filtered and the filtrate was diluted with water (20 mL ₎ and extracted with DCM (50 mL x 3). The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The residue was triturated with MeCN to afford the title compound (400 mg, 60%) as a white solid. LCMS: m/z＝364.2[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ4.51 (br s, 1H), 3.74 (d, J＝12.4Hz, 2H), 3.56 (br s, 1H), 2.92-2.84 (m, 4H), 2.69 (t, J＝6.8Hz, 2H), 2.04-1 .97(m,2H),1.83-1.76(m,2H),1.52-1.33(m,17H).

Step 5-tert-butyl(l-((6-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl(l-((6-aminohexyl)sulfonyl)piperidin-4-yl)carbamate (236 mg, 651.6 μmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (120 mg, 434.4 μmol, CAS#835616-60-9) in NMP (5.0 mL) was added DIPEA (112.3 mg, 868.8 μmol) and the mixture was heated at 90 °C overnight. After completion, the mixture was directly purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 65/35, v/v, 0.1% HCOOH) to give the title compound (190 mg, 75%) as a yellow semisolid. LCMS: m/z=620.2 [M+H] ⁺ .

Step 6 - 4-((6-((4-aminopiperidin-1-yl)sulfonyl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (1-((6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate (100 mg, 161.4 μmol) and 4M HCl in dioxane (6.0 mL) was stirred at rt for 5 h. After completion, the mixture was concentrated under reduced pressure to give the title compound as a yellow oil (100 mg, >100%). LCMS: m/z=520.2 [M+H] ⁺ .

4-((10-((4-aminopiperidin-1-yl)sulfonyl)decyl)amino)-2-(2,6-dioxopiperidin-3-yl)iso Indoline-1,3-dione (Intermediate G2)

Step 1 - S-(10-(1,3-dioxoisoindolin-2-yl)decyl)thioacetate. To a solution of 2-(10-bromodecyl)isoindoline-1,3-dione (2.0 g, 5.46 mmol, CAS# 24566-80-1) in DMF (20.0 mL) was added KSAc (686 mg, 6.01 mmol) and the mixture was stirred at rt under _N2 for 2 h. After completion, the mixture was poured into water and extracted with EtOAc (30 mL x ₃ ). The combined organic phases were dried over _Na2SO4 and concentrated under reduced pressure to give the title compound (2.0 g, 100% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.84(dd,J＝5.4,3.2Hz,2H),7.70(dd,J＝5.6,3.0Hz,2H),3.67(t,J＝7.2Hz,2H),2.85(t,J＝7.2Hz,2H),2.31(s,3H),1.70-1.60(m,2 H),1.59-1.50(m,2H),1.35-1.25(m,12H).

Step 2 - 10-(1,3-dioxoisoindolin-2-yl)decane-1-sulfonyl chloride. To a solution of S-(10-(1,3-dioxoisoindolin-2-yl)hexyl)thioacetate (200 mg, 0.55 mmol) and 2M aqueous HCl (0.15 mL) in MeCN (5.0 mL) was added NCS (295.5 mg, 2.21 mmol) portionwise at 0°C and the mixture was allowed to warm to rt and stirred for 1 h. Upon completion, the mixture was poured into ice-cold water and extracted with EtOAc (10 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (280 mg) as an off-white solid. LCMS: m/z=386.1 [M+H] ⁺ .

Step 3-tert-Butyl(l-((10-(l,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl piperidin-4-ylcarbamate (110.8 mg, 0.55 mmol, CAS#73874-95-0) and _Et3N (675.0 mg, 6.67 mmol) in DCM (5.0 mL) at 0°C was added a solution of 10-(l,3-dioxoisoindolin-2-yl)hexane-l-sulfonyl chloride (280 mg, assumed 0.55 mmol). The mixture was allowed to warm to rt and stirred overnight. Upon completion, the mixture was concentrated under reduced pressure and the residue was triturated with MeOH. The solid was collected by filtration to give the title compound (40 mg, 13% over two steps) as a white solid. LCMS: m/z=450.2[M-Boc+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.84 (dd, J=5.4, 3.2Hz, 2H), 7.70 (dd, J=5.6, 3.2Hz, 2H), 4.46 (br s, 1H), 3.79-3.71 (m, 2H), 3.67 (t, J= 7.2Hz,2H),3.63-3.50(m,1H),2.94-2.83(m,4H),2.05-1.97(m,2H),1.81-1.74(m,2H),1.71-1.61(m,2H),1.52-1.24(m,23H).

Step 4-tert-Butyl (1-((10-aminohexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl (1-((10-(1,3-dioxoisoindolin-2-yl)hexyl)sulfonyl)piperidin-4-yl) _carbamate (350 mg, 0.64 mmol) in DCM/EtOH ( _2/1 , 15.0 mL) was added _N2H4.H2O (98%, 127.5 mg, 2.55 mmol) and the mixture was heated at 50 °C overnight. After completion, the mixture was filtered and the filtrate was poured into 1 M NaOH aqueous solution and extracted with DCM (10 mL x 3). _The combined organic layers were dried over _Na2SO4 and concentrated under reduced pressure. The residue was triturated with MeCN, filtered and the filtrate was concentrated under reduced pressure to give the title compound (160 mg, 60%) as a white solid. LCMS: m/z = 420.3 [M+H] ⁺ .

Step 5-tert-Butyl(l-((10-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl(l-((10-aminohexyl)sulfonyl)piperidin-4-yl)carbamate (160 mg, 0.38 mmol) and 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (105.3 mg, 0.38 mmol, CAS#835616-60-9) in NMP (3.0 mL) was added DIPEA (98.4 mg, 0.76 mmol) and the mixture was heated at 90 °C overnight. After completion, the mixture was cooled to rt and directly purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 90/10, v/v, 0.1% HCOOH) to give the title compound as a yellow solid (40 mg, 16%). LCMS: m/z=576.3 [M-Boc+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.13 (br s, 1H), 7.49 (dd, J=8.4, 7.2 Hz, 1H), 7.08 (d, J=7.0 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.22 (br s, 1H), 4.93 (d, J=12.0, 5.3 Hz, 1H), 4.49 (br s, 1H). s,1H),3.81-3.68(m,2H),3.63-3.50(m,1H),3.26(t,J＝7.0Hz,2H),2.92-2.68(m,6H),2.03-1.98(m,2H),1.83-1.76(m,2H),1.69-1.64(m,2H),1 .53-1.27(m,25H).

Step 6 - 4-((10-((4-aminopiperidin-1-yl)sulfonyl)hexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. A mixture of tert-butyl (1-((10-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)sulfonyl)piperidin-4-yl)carbamate (36 mg, 0.053 mmol) and 4M HCl in dioxane (6.0 mL) was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to give the title compound (30 mg, 94%) as a yellow oil. LCMS: m/z=576.3 [M+H] ⁺ .

4-((14-((4-aminopiperidin-1-yl)sulfonyl)tetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl) Isoindoline-1,3-dione (Intermediate G3)

Step 1-2-(14-bromotetradecane)isoindoline-1,3-dione. To a solution of 1,14-dibromotetradecane (900 mg, 2.53 mmol, CAS#37688-96-3) in DMF (20 mL) was added phthalimide potassium salt (471 mg, 2.53 mmol, CAS#1074-82-4) at rt and the mixture was stirred at 30°C overnight. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1, v/v) to give the title compound (600 mg, 56% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.92-7.77(m,4H), 3.59-3.47(m,6H), 1.85-1.70(m,4H), 1.62-1.53(m,2H), 1.40-1.31(m,4H), 1.28-1.24(m,12H).

Step 2-(14-(1,3-dioxoisoindolin-2-yl)tetradecyl)S-thioacetate. To a solution of 2-(14-bromotetradecyl)isoindolin-1,3-dione (600 mg, 1.42 mmol) in DMF (20 mL) was added KSAc (485 mg, 4.26 mmol) and the mixture was stirred at rt for 2 h. After completion, the mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (550 mg, 93% yield) as a yellow solid. LCMS: m/z=440.2[M+Na] ⁺ .

Step 3 - 14-(1,3-dioxoisoindolin-2-yl)tetradecane-1-sulfonyl chloride. To a solution of S-(14-(1,3-dioxoisoindolin-2-yl)tetradecane)thioacetate (550 mg, 1.32 mmol) in MeCN (20 mL) was added 2M aqueous HCl (2 mL) and NCS (705 mg, 5.28 mmol) at 0°C and the mixture was stirred at rt for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×3). The combined organic phases were washed with saturated aqueous NaHCO ₃ solution (40 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (500 mg, 86% yield) as a yellow solid. LCMS: m/z=442.2 [M+H] ⁺ .

Step 4-tert-Butyl(l-((14-(l,3-dioxoisoindolin-2-yl)tetradecane)sulfonyl)piperidin-4-yl)carbamate. To a solution of 14-(l,3-dioxoisoindolin-2-yl)tetradecane-l-sulfonyl chloride (500 mg, 1.13 mmol) in DCM (10 mL) was added tert-butyl piperidin-4-ylcarbamate (272 mg, 1.36 mmol, CAS#73874-95-0) and _Et3N (229 mg, 2.26 mmol) and the mixture was stirred at rt for 2 h. After completion, the solvent was removed under reduced pressure and the residue was triturated with MeOH (20 mL), filtered and the filtrate was concentrated under reduced pressure to give the title compound (300 mg, 44% yield) as a white solid. LCMS: m/z = 506.3 [M-Boc+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.89-7.80(m,4H),6.88(d,J＝8.0Hz,1H),3.55(t,J＝7.2Hz,2H),3.52-3.45(m,3H),3.00-2.93(m,2H),2.89-2.80(m,2H),1.8 2-1.71(m,2H),1.69-1.51(m,4H),1.46-1.18(m,31H).

Step 5-tert-butyl(l-((14-aminotetradecyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl(l-((14-(1,3-dioxoisoindolin-2-yl)tetradecyl)sulfonyl)piperidin-4-yl) _carbamate (300 mg, 0.50 mmol) in DCM/ethanol (5 mL _{/2.5 mL) was added N2H4.H2O (} 98%, 250 mg, 5.0 mmol) and the mixture was heated at 50 °C for 2 days. After completion, the mixture was filtered and the filtrate was poured into water (50 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with saturated aqueous _NaHCO3 solution (40 mL), dried _{over Na2SO4} and concentrated under reduced pressure to afford the title compound (200 mg, 85% yield) as a white solid. LCMS: m/z = 476.4 [M+H] ⁺ .

Step 6-tert-Butyl(l-((14-((2-(2,6-dioxopiperidin-3-yl)-l,3-dioxoisoindolin-4-yl)amino)tetradecyl)sulfonyl)piperidin-4-yl)carbamate. To a solution of tert-butyl(l-((14-(l,3-dioxoisoindolin-2-yl)tetradecyl)sulfonyl)piperidin-4-yl)carbamate (200 mg, 0.42 mmol) in NMP (5 mL) were added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-l,3-dione (116 mg, 0.42 mmol, CAS#835616-60-9) and DIPEA (108 mg, 0.84 mmol) and the mixture was heated at 90 °C overnight. After completion, the mixture was cooled to rt and directly purified by C18 reverse phase chromatography (Biotage, MeCN/H ₂ O, 92/8, v/v, 0.1% HCOOH) to give the title compound as a yellow solid (140 mg, 46% yield). LCMS: m/z=732.3 [M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.1(s,1H),7.62-7.53(m,1H),7.08(d,J＝8.6Hz,1H),7.01(d,J＝7.0Hz,1H),6.91-6.85(m,1H),6.51(t,J＝6.4Hz,1H),5.04( dd,J＝13.0,5.2Hz,1H),3.52-3.44(m,2H),3.43-3.33(m,1H),3.33-3.24(m,2H),3.01-2.94(m,2H),2.89 -2.80(m,3H),2.62-2.51(m,1H),2.17(t,J＝8.2Hz,2H),1.95-1.86(m,2H),1.80 1.73(m,2H),1.67-1.52(m,5H),1.41-1.20(m,28H).

Step 7 - 4-((14-((4-aminopiperidin-1-yl)sulfonyl)tetradecyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride. To a solution of tert-butyl (1-((14-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)tetradecyl)sulfonyl)piperidin-4-yl)carbamate (140 mg, 0.19 mmol) in dioxane (2 mL) was added 4M HCl in dioxane (4 mL) and the mixture was stirred at rt for 2 h. Upon completion, the mixture was concentrated under reduced pressure to give the title compound (110 mg, 88% yield) as a yellow solid. LCMS: m/z=632.3 [M+H] ⁺ .

6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido [2,3-d]pyrimidin-7(8H)-one (Intermediate L1)

Step 1 - tert-Butyl 4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate. To a solution of 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (65 mg, 0.17 mmol, intermediate K) in 2-Me-THF (5 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (69.7 mg, 0.35 mmol, CAS#87120-72-7) and the mixture was stirred at 30° C. overnight. After completion, the mixture was diluted with water and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/1, v/v) to give the title compound (40 mg, 47% yield) as a white solid. LCMS m/z＝492.2[MH] ^-及476.2[MH ₂ O+H] ⁺ ； ¹ H NMR(400MHz,DMSO-d ₆ )δ8.72(s,1H),8.05(s,2H),6.85(t,J＝55.4Hz,1H),5.90-5.81(m,1H),4.26(br s,1H),4.08-3.87(m,2H),3.23-3.17(m,1H),2.94-2.81(m,2H),2.26-2.14(m,1H),2.07-1.79(m,6H),1.76-1.63(m,1H),1.54-1.38(m,11H),1.00(s,3H)。

Step 2 - 6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride. A mixture of tert-butyl 4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (160 mg, 0.32 mmol) and 4M HCl in dioxane (5 mL) was stirred at rt for 1 h. Upon completion, the mixture was concentrated under reduced pressure and the residue was triturated with ether to give the title compound as a yellow solid (126 mg, 92%). LCMS m/z = 376.3 [MH ₂ O+H] ⁺ .

4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyridine (2,3-d)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride (Intermediate L2)

Step 1 - 2-((4-(Benzylthio)-2-methylphenyl)amino)-6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one. A mixture of 4-(phenylmethylthio)-2-methylaniline (590 mg, 2.6 mmol, intermediate M), 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.3 mmol, intermediate K) and TFA (1.48 g, 13 mmol) in isopropanol (20 mL) was heated at reflux for 6 h. After completion, the mixture was cooled to rt, poured into water (100 mL), and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=3/1, v/v) to give the title compound (200 mg, 29% yield) as a brown solid. LCMS m/z＝523.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.49 (s, 1H), 8.83 (s, 1H), 8.13 (s, 1H), 7.40-7.15 (m, 8H), 6.89 (t, J＝55.2Hz, 1H), 5.74-5.63 (m, 1H), 4.29(s,1H),4.23(s,2H),2.43-2.31(m,1H),2.19(s,3H),2.05-1.94(m,1H),1.92-1.60(m,3H),1.53-1.41(m,1H),0.93(s,3H).

Step 2 - 4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride. To a solution of 2-((4-(phenylmethylthio)-2-methylphenyl)amino)-6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.38 mmol) in MeCN (5 mL) was added AcOH/water (0.4 mL/0.8 mL) at 0°C, and the mixture was stirred at 0°C for 5 min. Subsequently, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (150 mg, 0.76 mmol, CAS#118-52-5) was added, and the mixture was stirred at 0°C for another 30 min. After completion, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with saturated aqueous NaHCO ₃ solution (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound (180 mg, 94% yield) as a brown solid. LCMS m/z＝499.1[M+H] ⁺ . 1H NMR (400MHz, DMSO-d ₆ ) δ9.50 (s, 1H), 8.84 (s, 1H), 8.14 (s, 1H), 7.49-7.41 (m, 2H), 7.26-7.21 (m, 1H), 6.89 (t, J = 55.2Hz, 1H), 5.82-5.68 (m, 1H), 2. 44-2.31(m,1H),2.31-2.18(m,1H),2.25(s,3H),1.58-1.47(m,4H),0.97(s,3H).

4-((5-Bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride (Intermediate L3)

Step 1 - 2-((2-((4-(phenylmethylthio)-2-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)-6-fluorobenzamide. A mixture of 4-(phenylmethylthio)-2-methylaniline (2.0 g, 8.7 mmol, intermediate M), 2-((5-bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide (3.0 g, 8.7 mmol, intermediate N) and TFA (19.8 g, 87 mmol) in isopropanol (50 mL) was heated under reflux overnight. After completion, the mixture was cooled to rt and poured into water (200 mL). The resulting precipitate was collected by filtration and washed with ether (20 mL×3) to give the title compound (1.8 g, 38% yield) as a white solid. LCMS m/z＝538.2,540.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.2 (s, 1H), 8.78 (s, 1H), 8.20 (s, 1H), 8.16-8.04 (m, 3H), 7.42-7.28 (m, 5H), 7.28-7.20 (m, 2 H), 7.16 (dd, J = 8.4, 2.4Hz, 1H), 7.13-7.02 (m, 1H), 6.92 (t, J = 9.2Hz, 1H), 4.23 (s, 2H), 2.14 (s, 3H).

Step 2 - 4-((5-bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride. To a solution of 2-((2-((4-(phenylmethylthio)-2-methylphenyl)amino)-5-bromopyrimidin-4-yl)amino)-6-fluorobenzamide (1.0 g, 1.86 mmol) in MeCN (20 mL) was added AcOH/ _H2O (4 mL/8 mL) at 0°C, and the mixture was stirred at 0°C for 5 min. Subsequently, 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (733 mg, 3.72 mmol, CAS #118-52-5) was added, and the mixture was stirred at 0°C for _another 30 min. Upon completion, the mixture was diluted with EtOAc (200 mL), washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was triturated with ether (10 mL×3) to give the title compound (500 mg, 52% yield) as a white solid. LCMS m/z=514.1, 516.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.9 (s, 1H), 9.86 (s, 1H), 8.35 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.48 (dd, J=8.1, 2.0 Hz, 1H), 7.38-7.27 (m, 3H), 7.07 (t, J=9.2 Hz, 1H), 2.20 (s, 3H).

[1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (Intermediate G)

[0136] Step 1 - 5-Oxotetrahydrofuran-2-carboxylic acid. To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS #617-65-2) in _H2O (800 mL) and HCl (12 M, 210 mL) was added a solution of _NaNO2 (147 g, 2.13 mol) in _H2O (400 mL) at -5°C. The mixture was stirred at 15°C for 12 hr. Upon completion, the mixture was concentrated and then dissolved in EA (500 mL) and _filtered , and washed with EA (3 x 100 mL). The filtrate and washing solution were dried over _Na2SO4 , filtered and concentrated in vacuo to give the title compound (200 g, crude) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.43(s,1H),5.02-4.95(m,1H),2.67-2.38(m,4H)

Step 2 - N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide. To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was added _SOCl2 (246 g, 2.07 mol) slowly at 0°C. The mixture was stirred at 85°C for 3 hrs, and then the mixture was stirred at 15°C for 6 hrs. The mixture was concentrated in vacuo. The residue was dissolved in anhydrous DCM (1 L) at 0°C under _N2 . After that, a solution of _Et3N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, and then the mixture was stirred at 15°C for 3 hrs. After completion, water (600 mL) was added and the mixture was extracted with DCM (3 x 300 mL). The combined organic phases were washed with 0.5M HCl (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. ² .59-2.54(m,2H),2.40-2.38(m,1H); LC-MS(ESI ⁺ )m/z 272.0 ₍ M+Na) ⁺ .

Step 3 - 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. A solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to -78°C. Subsequently, a solution of t-BuOK (62.7 g, 559 mmol) in anhydrous THF (1000 mL) was added dropwise at -78°C under nitrogen atmosphere. The resulting reaction mixture was stirred at -40°C for 1 hr. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl solution (100 mL). The mixture was extracted with ethyl acetate (3×1500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA=1:1) to give the title compound (128 g, 92% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.32 (m, 2H), 6.89-6.81 (m, 2H), 4.91 (s, 2H), 4.17-4.11 (m, 1H), 3.80 (s, 3H), 3.54 (s, 1H), 2.98-2.87 (m, 1H), 2.73-2.60 (m, 1H), 2.26-2.20 (m, 1H), 1.80 (dq, J=4.8, 13.1 Hz, 1H).

Step 4-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl] trifluoromethanesulfonate. To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethanesulfonyl triflate (73.0 g, 258 mmol) dropwise at 0°C. The mixture was stirred at -10°C under _N2 for 1.5 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=20:1/8:1) to give the title compound (45.0 g, 68% yield) as a light yellow gum. ^1. _41-2.35 (m,2H).

3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (intermediate Object

Step 1 - 2-Bromo-N-methyl-6-nitro-aniline. To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS# 58534-94-4) in THF (40 mL) was added _MeNH2 (2M, 400 mL). The reaction mixture was stirred at 60 °C for 12 hours. Upon completion, the reaction mixture was poured into sat. _NaHCO3 (30 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL ₎ , dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound as a red oil (40.0 g, 95% yield). LC-MS (ESI ⁺ ) m/z 230.9 (M+H) ⁺ .

Step 2 - 3-Bromo-N2-methyl-benzene-1,2-diamine. To a mixture of 2-bromo-N-methyl-6-nitro-aniline (23.0 g, 99.5 mmol) in EA (300 mL) and _H2O (10 mL) was added AcOH (100 mL). The mixture was warmed to 50°C. Fe (22.2 g, 398 mmol ₎ was then added to the reaction mixture and the mixture was heated to 80°C for about 4 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo to give the title compound (20.0 g, 99% yield) as a red oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 6.73-6.70 (m, 1H), 6.68-6.60 (m, 2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58 (s, 3H).

Step 3- to 4- bromo-3-methyl -1H- benzimidazole -2- ketone. To a mixture of 3- bromo-N2-methyl-benzene -1,2- diamine (20.0g, 99.4mmol) ACN (300mL) solution CDI (32.2g, 198mmol) was added. The reaction mixture was stirred at 85 ° C under _N2 atmosphere for 12 hours. After completion, the reaction mixture was concentrated in vacuo. The reaction mixture was diluted with water (200mL), wherein a solid precipitate was formed, which was filtered off. The solid was washed with water (1L) and dried in vacuo to give the title compound (20.0g, 88% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.17 (s, 1H), 7.14 (dd, J = 1.2, 8.0Hz, 1H), 7.00-6.95 (m, 1H), 6.93-6.87 (m, 1H), 3.55 (s, 3H).

Step 4-3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8 mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reaction mixture was stirred at 0° C. for 0.5 hr. Afterwards, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (20.1 g, 52.8 mmol, intermediate G) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at 20° C. under N ₂ for 0.5 hr. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (13.3 g, 55% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38 (d, J = 8.8Hz, 2H), 7.22 (d, J = 8.0Hz, 1H), 6.84 (d, J = 8.8Hz, 2H), 6.80 (t, J = 8.0Hz, 1H), 6.48-6.40 (d, J = 8.0Hz, 1H), 5.22 (dd, J = 5. 2,12.8Hz,1H),5.04-4.93(m,2H),3.81(s,3H),3.80(s,3H),3.12-2.98(m,1H),2.93-2.77(m,1H),2.62(dq,J＝4.4,13.2Hz,1H),2.20-2.17(m,1H).

Step 5 - 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. A mixture of 3-(4-bromo-3-methyl- _{2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with N2} three times, and then the mixture was stirred at 120 °C under _N2 atmosphere for 2 hr. After completion, the reaction mixture was concentrated in vacuo to remove toluene. To the residue was added 200 mL of ice water, and then a white solid precipitate was formed. The mixture was filtered and the filter cake was collected and dried under vacuum to give the title compound as a white solid (7.30 g, 74% yield). ^1H NMR (400 MHz, DMSO-d ₆ )δ11.13(s,1H),7.25(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.05-6.93(m,1H),5.41(dd,J＝5.2,12.8Hz,1H),3.64(s,3H),2.96-2.83(m,1H),2.78-2. 59(m,2H),2.08-2.00(m,1H).

5-Bromo-3-methyl-1H-benzimidazol-2-one (Intermediate I)

[0136] Step 1 - 5-Bromo-N-methyl-2-nitro-aniline. 4-Bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS #321-23-3) was added to a solution of methylamine in tetrahydrofuran (2M, 1.51 _L ). The mixture was stirred at 15 °C for 10 minutes. Upon completion, the mixture was diluted with _H2O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over _Na2SO4 , filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. ¹ HNMR (400MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H).

Step 2 - 4-Bromo-N2-methyl-benzene-1,2-diamine. To a mixture of 5-bromo-N-methyl-2-nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and _H2O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50 °C and then Fe (174 g, 3.11 mol) was added to the reaction mixture. After that, the reaction mixture was stirred at 80 °C for 6 _hours . Upon completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was diluted with _H2O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with aq. _NaHCO3 and brine (300 mL), dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as a black oil. ¹ HNMR (400MHz, DMSO-d ₆ ) δ 6.55-6.52 (m, 1H), 6.48-6.45 (m, 1H), 6.43-6.42 (m, 1H), 4.89-4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d, J = 4.0Hz, 3H).

Step 3 - 5-Bromo-3-methyl-1H-benzimidazol-2-one. To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol) in CH ₃ CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture was stirred at 80 °C under N ₂ for 6 hours. Upon completion, the mixture was concentrated in vacuo. The mixture was diluted with H ₂ O (1.0 L) and filtered. The filter cake was washed with water (3×200 mL) and dried in vacuo to give the title compound (106 g, 85% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.33 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.27 (s, 3H).

3-(5-Bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (Intermediate J)

Step 1 - 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6 mmol, Intermediate I) in THF (300 mL) was added t-BuOK (3.63 g, 32.3 mmol) at 0°C. The mixture was stirred at 0-10°C under _N2 for 1 hour. A solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (9.87 g, 25.9 mmol, Intermediate G) in THF (100 mL) was then added to the reaction mixture at 0-10°C over 30 minutes. The mixture was stirred at 0-10°C under _N2 for 30 minutes. An additional solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (2.47 g, 6.47 mmol) in THF (20 mL) was added dropwise to the reaction mixture at 0-10 ° C. The mixture was then stirred for another 30 minutes at 0-10 ° C under N _2. After completion, the reactant was quenched with water (400 mL) and extracted with EA (3×200 mL). The combined organic layers were concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound (6.70 g, 67% yield) as a light yellow solid. The filtrate was also concentrated in vacuo and the residue was purified by column chromatography to give another batch of the title compound (1.80 g, 18% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.47(d,J＝1.6Hz,1H),7.21-7.16(m,3H),7.01(d,J＝8.0Hz,1H),6.85(d,J＝8.8Hz,2H),5.55-5.51(m,1H),4.84-4.73(m,2H),3 .72(s,3H),3.33(s,3H),3.04-3.00(m,1H),2.83-2.67(m,2H),2.07-2.05(m,1H).

Step 2 - 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione. To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was added methanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15 °C). The mixture was stirred at 120 °C for 2 hours. After completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice/water (200 mL) and extracted with EA (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound as an off-white solid (4.20 g, 67% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 5.40-5.35 (m, 1H), 2.34 (s, 3H), 2.92-2.88 (m, 1H), 2.71-2.60 (m, 2H), 2.03-1.99 (m, 1H).

6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3- d]pyrimidin-7(8H)-one (Intermediate K)

Step 1-(4-chloro-2-(methylthio)pyrimidin-5-yl)methanol. To a solution of _{ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (40.0 g, 172 mmol, CAS#5909-24-0) in THF (600 mL) at -78 °C under N2} was added DIBAL-H (1 M in THF, 517 mL, 517 mmol) and the mixture was allowed to warm to rt and stirred for 0.5 h. Upon completion, the reaction was quenched with saturated aqueous _NH4Cl solution (1000 mL) and extracted with EtOAc (1000 mL x 2). The combined organic layers were washed with brine, dried _{over Na2SO4} and concentrated under reduced pressure. The residue was triturated with petroleum ether to give the title compound (28.5 g, 87% yield) as a white solid. LCMS: m/z=191.1[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.61 (s, 1H), 4.50 (s, 2H), 2.52 (s, 3H).

Step 2-(1R,2R)-2-((5-(Hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol. To a solution of (4-chloro-2-(methylthio)pyrimidin-5-yl)methanol (12.0 g, 63.0 mmol) in i-PrOH (200 mL) was added (1R,2R)-2-amino-1-methylcyclopentan-1-ol (7.96 g, 69.4 mmol, CAS# 1400689-45-3) and DIPEA (24.0 g, 189 mmol) and the mixture was heated at 90 °C under _N2 overnight. Upon completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc = 5/1, v/v) to give the title compound (11.0 g, 65% yield) as a white solid. LCMS: m/z=270.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.82 (s, 1H), 6.33 (d, J = 8.0Hz, 1H), 5.29 (t, J = 5.3Hz, 1H), 4.68 (s, 1H), 4.36 (d, J = 5.4Hz, 2H), 4.33- 4.23(m,1H),2.42(s,3H),2.19-2.10(m,1H),1.72-1.55(m,4H),1.52-1.41(m,1H),1.09(s,3H).

[0136] Step 3 - 4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde. To a solution of (1R,2R)-2-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)-1-methylcyclopentan-1-ol (2.7 g, 10 mmol) in EtOAc (70 mL) was added _MnO2 (13.1 g, 150 mmol) and the mixture was heated at 50 °C under _N2 overnight. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (2.3 g, 86% yield) as a white solid. LCMS: m/z＝268.0[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.75 (s, 1H), 8.65 (d, J＝8.6Hz, 1H), 8.54 (s, 1H), 4.76 (s, 1H), 4.42-4.34 (m, 1H), 2.52 (s, 3H), 2.2 8-2.15(m,1H),1.77-1.57(m,4H),1.48-1.37(m,1H),1.16(s,3H).

Step 4 - 8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To _a solution of 4-(((1R,2R)-2-hydroxy-2-methylcyclopentyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (2.3 g, 8.6 mmol) and EtOAc (2.27 g, 25.8 mmol) in anhydrous THF (25 mL) was added LiHMDS (1 M in THF, 25.8 mL, 25.8 mmol) dropwise at -10 °C under N2. The mixture was allowed to warm to rt and stirred overnight. Upon completion, the reaction was quenched with saturated aqueous _NH4Cl solution and extracted with EtOAc (50 mL x 3 ₎ . The combined organic phases were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5/1, v/v) to give the title compound (2.1 g, 84% yield) as a yellow solid. LCMS: m/z＝291.9[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 7.89 (d, J = 9.4Hz, 1H), 6.57 (d, J = 9.4Hz, 1H), 5.93-5.84 (m, 1H), 4.53 (s, 1H), 2.60 (s, 3H ),2.45-2.34(m,1H),2.26-2.15(m,1H),2.04-1.94(m,1H),1.91-1.82(m,2H),1.71-1.64(m,1H),0.95(s,3H).

Step 5 - Ethyl 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetate. To _a solution of 8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.34 mmol) in anhydrous dioxane (5 mL) under N2 was added _BrCF2COOEt (139.3 mg, 0.69 mmol, CAS#667-27-6), Pd(MeCN) _2Cl2 (8.9 _mg , 0.034 mmol), Xantphos (39.7 mg, 0.069 _mmol ) and _K2CO3 (94.9 mg, 0.69 mmol) and the mixture was heated under reflux overnight. After completion, the mixture was cooled to rt, poured into water, and extracted with EtOAc (30 mL×3). The combined organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=2/1, v/v) to give the title compound (70 mg, 49% yield) as a white solid. LCMS: m/z=414.1[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ8.73 (s, 1H), 8.03 (s, 1H), 5.91-5.85 (m, 1H), 4.41-4.31 (m, 2H), 2.79-2.68 (m, 1H), 2.65 (s, 3H), 2.2 9-2.19(m,1H),2.11-1.88(m,3H),1.85-1.78(m,1H),1.31(t,J=7.2Hz,3H),1.12(s,3H).

Step 6 - 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetic acid. To a solution of ethyl 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetic acid (65 mg, 0.16 mmol) in MeOH/H ₂ O (4 mL/1 mL) was added K ₂ CO ₃ (43.5 mg, 0.31 mmol) and the mixture was stirred at rt for 2 h. After completion, the mixture was adjusted to pH 3 with 1 M aqueous HCl solution and extracted with EtOAc (30 mL×4). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the title compound as a yellow solid (50 mg, 82% yield). LCMS: m/z = 386.1 [M+H] ⁺ .

Step 7 - 6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 2,2-difluoro-2-(8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)acetic acid (330 mg, 0.86 mmol) in NMP (10 mL) was added KF (248.5 mg, 4.28 mmol) and the mixture was heated at 150 °C for 2.5 h. After completion, the mixture was cooled to rt, poured into water (50 mL), and extracted with EtOAc (50 mL x ₄ ). The combined organic phases were washed with brine, dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=5/1, v/v) to give the title compound (110 mg, 38% yield) as a white solid. LCMS: m/z=342.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (s, 1H), 7.94 (s, 1H), 6.80 (t, J=54.8 Hz, 1H), 5.92-5.85 (m, 1H), 2.82-2.73 (m, 1H), 2.65 (s, 3H), 2.32-2.22 (m, 1H), 2.13-2.01 (m, 2H), 2.00-1.91 (m, 1H), 1.90-1.82 (m, 1H), 1.15 (s, 3H).

Step 8-6-(Difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (110 mg, 0.32 mmol) in 2-Me-THF/H ₂ O (5 mL/1 mL) was added potassium persulfate (495.2 mg, 0.81 mmol) and the mixture was stirred at 30° C. for 3 h. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL×4). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether/EtOAc=1/1, v/v) to give the title compound (60 mg, 50% yield) as a white solid. LCMS: m/z=356.1 [MH ₂ O+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ9.08 (s, 1H), 8.10 (s, 1H), 6.84 (t, J=54.4 Hz, 1H), 5.85-5.76 (m, 1H), 3.41 (s, 3H), 2.82-2.72 (m, 1H), 2.35-2.24 (m, 1H), 2.18-2.07 (m, 2H), 2.02-1.88 (m, 2H), 1.13 (s, 3H).

4-(Benzylthio)-2-methylaniline (Intermediate M)

Step 1-Benzyl(3-methyl-4-nitrophenyl)sulfane. To a solution of 4-chloro-2-methyl-1-nitrobenzene (10 g, 58 mmol, CAS#5367-28-2) in ethanol (200 mL) was added KOH (3.6 g, 64 mmol) and BnSH (7.9 g, 64 mmol, CAS#100-53-8) and the mixture was heated at 70 °C overnight. After completion, the mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1, v/v) to give the title compound (10 g, 67% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.93 (d, J=8.6 Hz, 1 H), 7.46-7.23 (m, 7H), 4.39 (s, 2H), 2.50 (s, 3H).

Step 2 - 4-(Benzylthio)-2-methylaniline. To a solution of benzyl(3-methyl-4-nitrophenyl)sulfane (9.0 g, 34.7 mmol) in ethanol (100 mL) was added Fe (1.9 g, 347 mmol) and saturated aqueous _NH4Cl solution (50 mL) and the mixture was heated at 70 °C for 2 h. After completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (7.0 g, 89% yield) as a brown solid. LCMS m/z＝230.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.30-7.16 (m, 5H), 6.95 (d, J＝2.2Hz, 1H), 6.89 (dd, J＝8.2, 2.2Hz, 1H), 6.52 (d, J＝8.2Hz, 1H), 4.97 (s, 2H) ,3.94(s,2H),1.99(s,3H).

2-((5-Bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide (Intermediate N)

To a solution of 5-bromo-2,4-dichloropyrimidine (8.25 g, 36.2 mmol, CAS#36082-50-5) in isopropanol (50 mL) was added 2-amino-6-fluorobenzamide (5.02 g, 32.5 mmol, CAS#115643-59-9) and DIPEA (21.1 g, 162.9 mmol) and the mixture was heated at reflux under _N2 for 18 h. Upon completion, the mixture was cooled to rt, _dried over _Na2S04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether/EtOAc=10/1 to 3/1, v/v) to give the title compound (5.9 g, 48% yield) as a white solid. LCMS m/z＝345.0,347.0[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.6 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 8.09 (d, J = 8.2Hz, 1H), 7.62-7.53 (m, 1H), 7.17-7.08(m,1H).

Non-8-yn-1-ylcarbamic acid tert-butyl ester (Intermediate O)

[0136] Step 1 - Non-8-yn-1-yl methanesulfonate. To a stirred solution of non-8-yn-1-ol (20.00 g, 142.6 mmol) and TEA (39.54 mL, 285.3 mmol) in DCM (200.0 mL) was added MsCl (24.51 g, 213.9 mmol) at 0°C under nitrogen atmosphere. The mixture was stirred at rt for 1 h. After completion, the mixture was quenched with water (150 mL) at rt. _The resulting mixture was extracted with _CH2Cl2 (2 x 50 mL). The combined organic layers were washed with NaCl aq (1 x 100 mL) and dried _over anhydrous _Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (30 g, 96% yield) as a light yellow oil. ¹ HNMR (400MHz, DMSO-d ₆ ) δ4.19(t,J＝6.5Hz,2H),3.16(s,3H),2.73(t,J＝2.7Hz,1H),2.16(td,J＝6.9,2.7Hz,2H),1.70-1.62(m,2H),1.49-1.42(m,2H),1. 40-1.26(m,6H).

Step 2 - 9-azidonon-1-yne. To a stirred solution of methanesulfonic acid non-8-yn-1-yl ester (30.00 g, 137.4 mmol) in DMF (100.00 mL) was added NaN ₃ (17.87 g, 274.8 mmol) at rt under nitrogen atmosphere. The mixture was stirred at 55 ° C for 16 h. After completion, the reactant was quenched with water at rt. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (30: 1) to give 9-azidonon-1-yne (21 g, 92% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ3.37-3.27(m,2H),2.73(t,J＝2.8Hz,1H),2.14(td,J＝6.9,2.6Hz,2H),1.56-1.49(m,2H),1.47-1.40(m,2H),1.39-1.24(m,6H) .

[0266] Step 3 - Non-8-yn-1-amine hydrochloride. To a stirred solution of 9-azidonon-1-yne (32.00 g, 193.7 mmol) in THF (300.0 mL)/ _H2O (30.00 mL) was added _PPh3 (76.19 g, 290.5 mmol) portionwise at 0°C under nitrogen atmosphere. The solution was stirred at 55°C for 4 h. Upon completion, the solution was concentrated under reduced pressure and diluted with DCM (300 mL). The mixture was acidified to pH 1 with HCl (2M aq.). The aqueous layer was extracted with DCM (3 x 100 mL). The aqueous layer was concentrated under reduced pressure to afford the title compound (27 g, 79% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.04 (s, 3H), 2.81-2.68 (m, 3H), 2.15 (td, J = 6.9, 2.7Hz, 2H), 1.59-1.51 (m, 2H), 1.50-1.39 (m, 2H), 1.39-1.23 (m, 6H). LC/MS (ESI, m/z): [(M+1)] ⁺ =140.2.

Step 4 - tert-Butyl N-(non-8-yn-1-yl)carbamate. To a stirred mixture of non-8-yn-1-amine hydrochloride (27.00 g, 153.7 mmol) in DCM (300.0 mL) was added TEA (106.5 mL, 768.4 mmol) dropwise at 0°C under nitrogen atmosphere. Subsequently, Boc ₂ O (50.31 g, 230.5 mmol) was added dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at rt for 16 h. After completion, the mixture was quenched with water (200 mL) at rt. The resulting mixture was extracted with CH ₂ Cl ₂ (2×100 mL), and the combined organic layers were dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:1) to give the title compound (20 g, 54% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.76(t,J＝5.7Hz,1H),2.90(q,J＝6.6Hz,2H),2.73(t,J＝2.6Hz,1H),2.15(td,J＝7.0,2.7Hz,2H),1.48-1.41(m,2H),1.41-1.32 (m,13H),1.30-1.17(m,4H). LC/MS (ESI, m/z): [(M+1-56)] ⁺ =184.2.

Carbonic acid (1R, 3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide 1H-pyrazol-3-yl)cyclopentylphenyl ester (Intermediate P)

Step 1-(1-(tert-butyl)-3-((1S,3R)-3-((phenoxycarbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl N-[2-tert-butyl-5-[(1S,3R)-3-hydroxycyclopentyl]pyrazol-3-yl]carbamate (1 g, 2.80 mmol, intermediate AG) and phenyl chloroformate (394 mg, 2.52 mmol) in DCM (14 mL) were added DMAP (34.2 mg, 279 μmol) and pyridine (663 mg, 8.39 mmol), and the mixture was then stirred at 25 °C for 12 h. Upon completion, the mixture was quenched with sat. _NH4Cl (20 mL), diluted with DCM (20 mL), and then washed with water (20 mL x 3) and brine (20 mL x 3). The solution was then dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 0/1) to give the title compound (1.2 g, 85% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.48-7.29 (m, 7H), 7.27-7.15 (m, 3H), 6.13 (br s, 1H), 5.29-5.22 (m, 1H), 5.21 (s, 2H), 3.17-3.06 (m, 1H), 2.66-2.55 (m, 1H), 2.14-2.07 (m, 1H), 2.04-1.85 (m, 4H), 1.59 (s, 9H).

Step 2 - (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylphenyl carbonate. To a solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-((phenoxycarbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (1 g, 2.09 mmol) in THF (25 mL) was added Pd/C (1.00 g, 943 μmol, 10 wt%) and the reaction mixture was placed under _H2 atmosphere. The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless gum (0.7 g, 98% yield). LCMS: tR = 0.417 min., (ES ⁺ ) m/z (M+H) ⁺ = 344.2

Step 3 - (1R,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentylphenyl carbonate. A solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylphenyl carbonate (0.7 g, 2.04 mmol), 5-(methoxymethyl)-2-methyl-pyrazole-3-carboxylic acid (416 mg, 2.45 mmol, intermediate AI), _T3P (3.89 g, 6.11 mmol, 50% solution in DMF), and DIEA (1.32 g, 10.2 mmol) in MeCN (8 mL) was stirred at 60 °C for 12 h. After completion, the mixture was quenched with sat. NH ₄ Cl (10 mL) and extracted with EtOAc (15 mL×2). The organic layer was washed with brine (10 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (0.7 g, 62% yield) as a brown oil. ¹ H NMR (400MHz, CDCl ₃ )δ=7.44(br s,1H),7.40-7.36(m,2H),7.26-7.22(m,1H),7.20-7.17(m,2H),6.63(br s,1H),6.30(s,1H),5.27-5.22(m,1H),4.49 (s,2H),4.20(s,3H),3.44(s,3H),3.20-3.11(m,1H),2.66-2.58(m,1H),2.17-2.07(m,2H),2.04(br s,1H),2.02-1.88(m,3H),1.65(s,9H).

1-(4-((2,2,2-trifluoroacetoxy)methyl)cyclohexyl)-1H-pyrazole-4-carboxylic acid (Intermediate Q)

Step 1 - tert-Butyl 1-(4-(ethoxycarbonyl)cyclohex-1-en-1-yl)-1H-pyrazole-4-carboxylate. To a solution of tert-butyl 1H-pyrazole-4-carboxylate (900 mg, 5.3 mmol, CAS#611239-23-7) and ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (1 g, 3.57 mmol, CAS#1049004-32-1) in pyridine (10 mL) was added Cu(OAc) ₂ (1.30 g, 7.14 mmol) at 20°C under nitrogen atmosphere. The reaction was then stirred at 100°C for 10 h. Upon completion, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic phase was washed with brine (2×10 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:7) to give the title compound (0.8 g, 69% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ -d) δ=7.99 (s, 1H), 7.90 (s, 1H), 6.29-6.28 (m, 1H), 6.29-6.17 (m, 1H), 4.24-4.12 (m, 2H), 2.81-2.31 (m, 5H), 2.28-2.17 (m, 1H), 2.11-1.86 (m, 1H), 1.56 (s, 8H), 1.29 (t, J=7.2 Hz, 3H).

Step 2-1-(4-(Hydroxymethyl)cyclohex-1-ene-1-yl)-1H-pyrazole-4-carboxylic acid tert-butyl ester. To a solution of tert-butyl 1-(4-ethoxycarbonylcyclohexene-1-yl)pyrazole-4-carboxylate (750 mg, 2.3 mmol) in THF (17 mL) was added DIBAL-H (1 M, 4.68 mL) at -20 ° C under a nitrogen atmosphere. The reactants were then stirred at -20 ° C under a nitrogen atmosphere for 0.5 h. Upon completion, the reactants were quenched with 5 mL of methanol and then stirred at 0 ° C for 30 min. The reactants were then dried over sodium sulfate, filtered, and the filtrate was concentrated to give a residue. The title compound (0.6 g, 92% yield) was obtained as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ -d) δ = 7.99 (s, 1H), 7.90 (s, 1H), 6.30-6.12 (m, 1H), 3.68-3.55 (m, 2H), 2.77-2.63 (m, 1H), 2.61-2.47 (m, 1H), 2.43-2.32 (m, 1H) ,2.14-1.84(m,4H),1.56(s,10H).

Step 3 - tert-Butyl 1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxylate. To a solution of Pd/C (1.90 g, 1.80 mmol, 10 wt%) in MeOH (20 mL) _under N was added tert-butyl 1-[4-(hydroxymethyl)cyclohexen-1-yl]pyrazole-4-carboxylate (0.5 g, 1.8 mmol). The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred under _H (15 psi) at 20 °C for 10 h. Upon completion, the reaction was filtered to give a filtrate, which was filtered to give the title compound as a colorless oil (0.55 g). LC-MS (ESI ⁺ ) m/z 281.2 (M+H) ⁺ .

Step 4-1-(4-((2,2,2-trifluoroacetoxy)methyl)cyclohexyl)-1H-pyrazole-4-carboxylic acid. To a solution of tert-butyl 1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-carboxylate (0.55 g, 1.96 mmol) in DCM (10 mL) was added TFA (3.08 g, 27.01 mmol) at 0°C under nitrogen atmosphere. The reactants were then stirred at 20°C under nitrogen atmosphere for 4 h. Upon completion, the reactants were poured into ice water (10 mL) and extracted with dichloromethane (2×15 mL). The combined organic phases were washed with brine (2×10 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give the title compound (0.6 g) as a white solid. LC-MS (ESI ⁺ ) m/z 321.0 (M+H) ⁺ .

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole- 4-Formylamino)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate R)

Step 1-(1R,3S)-3-(1-(tert-butyl)-5-(1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (288 mg, 936 μmol, Intermediate U) and 1-[4-[(2,2,2-trifluoroacetyl)oxymethyl]cyclohexyl]pyrazole-4-carboxylic acid (300 mg, 936 μmol, Intermediate Q) in ACN (6 mL) were added _T3P (1.8 g, 2.8 mmol, 50% solution in DMF) and DIEA (605.3 mg, 4.6 mmol) at 0 °C under a stream of nitrogen. The reactant was then stirred at 20 ° C under a nitrogen atmosphere for 10 h. After completion, the reactant was poured into ice water (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase was washed with brine (2×10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-TLC (petroleum ether: ethyl acetate = 0: 1) to give the title compound (60 mg, 10% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 515.3 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-(hydroxymethyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of [(1R,3S)-3-[1-tert-butyl-5-[[1-[4-(hydroxymethyl)cyclohexyl]pyrazole-4-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (60.0 mg, 116.5 μmol) and TEA (35.4 mg, 349.7 μmol) in DCM (0.6 mL) was slowly added dropwise a solution of MsCl (110 mg, 960.27 μmol) in DCM (0.6 mL) at 0° C. under a nitrogen atmosphere. The reaction was then stirred at 0° C. under a nitrogen atmosphere for 2 h. After completion, the reaction was poured into saturated aqueous sodium bicarbonate solution (2 mL) at 0°C and extracted with dichloromethane (2 x 3 mL). The combined organic phases were washed with brine (2 x 2 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound as a colorless oil (60.0 mg). LC-MS (ESI ⁺ ) m/z 593.3 (M+H) ⁺ .

3-(3-methyl-4-((4-(methylamino)piperidin-1-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole oxazol-1-yl)piperidine-2,6-dione (Intermediate S)

This intermediate was synthesized as previously described in WO 2020/264499, WO 2020/264490, WO 2020/113233 and US 2019/192668.

2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid (Intermediate T)

Step 1-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyl]4-methylbenzenesulfonate. To a solution of 4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexanol (1 g, 2.71 mmol) and TosCl (517 mg, 2.71 mmol) was added pyridine (10 mL) at 0°C. The mixture was stirred at 0-20°C for 12 h. The mixture was then stirred at 40°C for 12 hr. Upon completion, the mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine (2×10 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 8/1) to give the title compound (1 g, 70% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.78 (d, J = 8.4Hz, 2H), 7.59 (dd, J = 1.6, 7.5Hz, 4H), 7.49-7.40 (m, 8H), 4.70 (br s, 1H), 3.46 (d, J = 5.8Hz, 2H), 2.41 (s, 3H), 1.74- 1.62(m,2H),1.58-1.44(m,5H),1.33-1.12(m,2H),1.00-0.95(m,9H).

Step 2 - tert-Butyl 2-[1-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetate. To a solution of tert-butyl 2-(1H-pyrazol-4-yl)acetate (300 mg, 1.65 mmol, intermediate AT) and [4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyl]4-methylbenzenesulfonate (1.72 g, 3.29 mmol) in DMSO (17 mL) was added KI (27.3 mg, 164 μmol) and KOH (277 mg, 4.94 mmol) at 20°C. The mixture was stirred at 50°C for 0.5 h. Upon completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (2×20 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The product was purified by flash silica gel chromatography ( 40g The residue was purified by HPLC-MS/MS (HPLC-MS/MS, HPLC-MS/MS, 5 min, 10% ethyl acetate/petroleum ether gradient, 80 mL/min) to afford the title compound as a yellow oil (180 mg, 20% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝7.65-7.57 (m, 5H), 7.49-7.42 (m, 6H), 7.29 (s, 1H), 5.64 (d, J＝1.8 Hz, 6H), 4.42 (t, J＝5.32 Hz, 3H), 3.70-3.46 (m, 2H), 3.36 (s, 2H), 1.80-1.51 (m, 17H), 1.45-1.38 (m, 9H), 1.03-0.99 (m, 9H).

Step 3 - 2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid. To a solution of tert-butyl 2-[1-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetate (180 mg, 337 μmol) in THF (1.5 mL) and H ₂ O (0.5 mL) was added LiOH.H ₂ O (70.8 mg, 1.69 mmol). The mixture was then stirred at 20° C. for 12 h. Upon completion, the mixture was poured into ice water (3 mL) and extracted with ethyl acetate (2×3 mL). The combined organic phases were washed with brine (2×3 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to give a residue. The product was purified by flash silica gel chromatography ( 4g The residue was purified by Silica Flash Column, eluent 0 to 25% ethyl acetate in petroleum ether gradient at 50 mL/min) to give the title compound (50 mg, 31% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.30-12.09 (m, 1H), 7.65-7.59 (m, 4H), 7.58-7.54 (m, 1H), 7.50-7.40 (m, 6H), 7.29 (s, 1H), 3.63-3.46 (m, 2H), 3.37 (s, 2 H),2.05-1.97(m,3H),1.87(br d,J=12.0Hz,1H),1.78-1.64(m,3H),1.62-1.53(m,2H),1.20-1.15(m,2H),1.05-0.95(m,9H).

Isopropylcarbamic acid (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (intermediate U)

Step 1-Benzyl(1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. A solution of benzyl(1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (300 mg, 839 μmol, Intermediate AG) and (4-nitrophenyl)chloroformate (254 mg, 1.26 mmol) in anhydrous DCM (5 mL) was treated with pyridine (199 mg, 2.52 mmol, 203 μL) and DMAP (10.3 mg, 83.9 μmol) and the reaction mixture was stirred at 20 °C for 16 hr. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (12 g The residue was purified by ELISA (Solution® Silica Flash Column, ethyl acetate/petroleum ether: 0 to 30%) to give the title compound (223 mg, 50% yield) as a yellow oil. LC-MS(ESI ⁺ )m/z523.1(M+H) ⁺ , ¹ H NMR(400MHz, CDCl ₃ )δ=8.31-8.24(m,2H),7.42-7.34(m,7H),6.32-6.21(m,1H),6.16(s,1H),5.30-5.23(m,1H),5.21( s,2H),3.22-3.09(m,1H),2.68-2.57(m,1H),2.19-2.09(m,1H),2.09-2.06(m,1H),2.04-1.95(m,3H),1.94-1.86(m,1H),1.60(s,9H).

Step 2-isobutyric acid (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester. A solution of [(1R,3S)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl](4-nitrophenyl) carbonate (220 mg, 421 μmol), propan-2-amine (32.4 mg, 547 μmol, 47.0 μL) and DIPEA (272 mg, 2.11 mmol, 367 μL) in THF (3 mL) was stirred at 20 °C for 4 h. After completion, the reaction mixture was diluted with EA (40 mL) and stirred for 5 min. The organic phase was washed with aq.NaOH (25 mL x 4, 1 M), brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (150 mg) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.38 (m, 5H), 6.38-5.99 (m, 2H), 5.21-5.19 (m, 2H), 5.15 (m, 1H), 4.55 (br s, 1H), 3.89-3.65 (m, 1H), 3.14-3.00 (m, 1H), 2.51-2.39 (m, 1H), 2.04-1.99 (m, 1H), 1.97-1.75 (m, 5H), 1.58 (s, 9H), 1.20-1.07 (m, 6H).

Step 3-(1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To _a solution of (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isobutyrate (150 mg, 339 μmol) in THF (2 mL) and EtOAc (4 mL) was added Pd/C (20 mg, 10 wt%) under N. The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred under a balloon of hydrogen (15 psi) at 20 °C for 4 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (4 g The residue was purified by HPLC-MS/MS (ESI ⁺ ) (HPLC-MS/MS/MS/ESI+) (M+H) ⁺ .

Methanesulfonic acid [4-[4-[2-[[2-tert-butyl-5-[(1S,3R)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazole- 3-yl]amino]-2-oxo-ethyl]pyrazol-1-yl]cyclohexyl]methyl ester (Intermediate V)

Step 1-[(1R,3S)-3-[1-tert-butyl-5-[[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate. To a solution of [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (64.7 mg, 209 μmol, intermediate U) and 2-[1-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetic acid (100 mg, 209 μmol, intermediate T) in pyridine (1 mL) was added EDCI (120 mg, 629 μmol) and DMAP (2.56 mg, 20.9 μmol) at 20 °C. The mixture was stirred at 50 °C for 12 h. After completion, the reactant was poured into ice water (2 mL) and extracted with ethyl acetate (2×2 mL). The combined organic phase was washed with brine (2×2 mL), dried over sodium sulfate, then filtered and concentrated to give a residue. The residue was purified by prep-TLC (SiO ₂ , EA:PE=4:1) to give the title compound (100 mg, 62% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=9.41 (s, 1H), 7.63-7.60 (m, 5H), 7.47-7.44 (m, 5H), 7.33 (s, 1H), 6.91 (br d,J＝8.0Hz,1H),5.89(s,1H),5.01-4.91(m,1H),4.13-3.98(m,3H),3.55-3.47(m,2H),3.44-3.41(m,2H),3.17(d,J＝5.12Hz,1H),2.34-2.32(m,1H ),1.95-1.77(m,6H),1.73-1.57(m,8H),1.26-1.14(m,6H),1.04-1.00(m,18H).

Step 2-[(1R,3S)-3-[1-tert-butyl-5-[[2-[1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]acetyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate. To a solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-[1-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyl]pyrazol-4-yl]acetyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (100 mg, 130 μmol) was added TBAF (1 mL, 1 M in THF). The mixture was stirred at 20 °C for 1 h. After completion, the mixture was concentrated to give a residue. The residue was purified by prep-TLC (SiO ₂ , EA:PE=8:1) to give the title compound (47 mg, 51% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 529.3 (M+H) ⁺ .

Step 3 - methanesulfonic acid [4-[4-[2-[[2-tert-butyl-5-[(1S,3R)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]amino]-2-oxo-ethyl]pyrazol-1-yl]cyclohexyl]methyl ester. To a solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-[1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]acetyl]amino]pyrazol-3-yl]cyclopentyl] N-isopropylcarbamate (35 mg, 66.2 μmol) and TEA (13.4 mg, 132 μmol) in DCM (0.5 mL) was slowly added dropwise, and the mixture was stirred at 0 °C for 1 h. Upon completion, the reaction mixture was quenched with NaHCO ₃ (saturated aqueous solution, 1 mL) at 0° C. and extracted with DCM (2×2 mL). The combined organic phases were washed with brine (2×2 mL), dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give the title compound as a yellow oil (30 mg). LC-MS (ESI ⁺ ) m/z 607.2 (M+H) ⁺ .

2-[2-(2-Prop-2-ynyloxyethoxy)ethyl]pyrazole-3-carboxylic acid (Intermediate W)

Step 1 - 2-(2-prop-2-ynyloxyethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-prop-2-ynyloxyethoxy)ethanol (6 g, 41.6 mmol, CAS# 7218-43-1) and 4-methylbenzenesulfonyl chloride (15.9 g, 83.2 mmol) in DCM (120 mL) was added TEA (21.1 g, 208 mmol) and DMAP (508 mg, 4.16 mmol). The mixture was then stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (120 mL) at 25 °C and then extracted with EtOAc (120 mL×3). The combined organic layers were washed with EtOAc (120 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) to give the title compound (10.9 g, 30.3 mmol, 73% yield) as an orange oil. LCMS: tR=0.546 min., (ES+) m/z (M+H)+=254.3.

Step 2 - 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid methyl ester and 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylic acid methyl ester. To a solution of 2-(2-prop-2-ynyloxyethoxy)ethyl 4-methylbenzenesulfonate (5.5 g, 18.4 mmol) and 1H-pyrazole-5-carboxylic acid methyl ester (2.79 g, 22.1 mmol) in DMF (55 mL) were added Cs ₂ CO ₃ (12.0 g, 36.8 mmol) and KI (306 mg, 1.84 mmol). The mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (60 mL) at 25° C. and then extracted with EtOAc (60 mL×3). The combined organic layers were washed with EtOAc (60 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250×50 mm×7 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-ACN]; B%: 16%-46%, 17 min) to give methyl 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (1 g, 22% yield) ( ¹ H NMR (400 MHz, DMSO-d6) δ = 7.58 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 4.66 (t, J = 5.6 Hz, 2H), 4.07 (d, J = 2.4 Hz, 2H), 3.82 (s, 3H), 3.73 (t, J = 5.6 Hz, 2H), 3.47 (s, 4H), 3.40 (t, J = 2.4 Hz, 1H) and 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylic acid methyl ester (1 g, 3.96 mmol, 22% yield) ( ¹ HNMR (400MHz, DMSO-d6) δ = 7.85 (d, J = 2.4Hz, 1H), 6.74 (d, J = 2.4Hz, 1H), 4.35 (t, J = 5.4Hz, 2H), 4.10 (d, J = 2.4Hz, 2H), 3.83-3.76 (m, 5H), 3.56-3.49 (m, 4H), 3 .41(t,J＝2.4Hz,1H).

Step 3 - 2-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-3-carboxylic acid. To a solution of methyl 2-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-3-carboxylate (1 g, 3.96 mmol) in THF (10 mL) and H ₂ O (2 mL) was added LiOH.H ₂ O (665 mg, 15.8 mmol). The mixture was stirred at 20° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (12 mL) at 25° C. and the pH was adjusted to less than 5 with HCl (1 M), followed by extraction of the solution with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (850 mg, 77% yield) as a white solid. LCMS: tR=0.337min., (ES+)m/z(M+H) ⁺ =239.0.

[(1R,3S)-3-[1-tert-butyl-5-[[2-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-3-carbonyl] [amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (Intermediate X)

To a solution of 2-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-3-carboxylic acid (840 mg, 3.53 mmol, intermediate W) and [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (1.20 g, 3.88 mmol, intermediate U) in MeCN (10 mL) were added T ₃ P (6.73 g, 50% solution in DMF) and DIEA (2.28 g, 17.6 mmol). The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25° C. and then extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (1 g, 53% yield) as an orange solid. LCMS: tR=0.652 min., (ES ⁺ ) m/z (M+H) ⁺ =529.2.

1-Undec-10-ynylpyrazole-4-carboxylic acid (Intermediate Y)

Step 1 - Undec-10-ynyl 4-methylbenzenesulfonate. To a solution of undec-10-yn-1-ol (2 g, 11.89 mmol) and TosCl (2.72 g, 14.3 mmol) in DCM (20 mL) was added TEA (3.61 g, 35.7 mmol) at 0°C. The mixture was then stirred at 20°C for 12 h. Upon completion, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine (2×30 mL), dried over sodium sulfate, filtered, and the filtrate was then concentrated to give a residue. The residue was purified by flash silica gel chromatography ( 40g The residue was purified by HPLC-MS/MS (HPLC-MS/MS, HPLC-MS/MS, 500 mL/min, eluent: 1% ethyl acetate/petroleum ether gradient, 100 mL/min) to afford the title compound as a white solid (3.27 g, 85% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.78 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.00 (t, J=6.4 Hz, 2H), 2.71 (t, J=2.6 Hz, 1H), 2.42 (s, 3H), 2.12 (dt, J=2.4, 6.8 Hz, 2H), 1.57-1.49 (m, 2H), 1.45-1.36 (m, 2H), 1.33-1.25 (m, 2H), 1.16 (br d, J=4.4 Hz, 8H).

Step 2-1-Undec-10-ynylpyrazole-4-carboxylic acid. To a solution of 4-methylbenzenesulfonic acid undec-10-ynyl ester (3 g, 9.30 mmol) and 1H-pyrazole-4-carboxylic acid methyl ester (1.41 g, 11.2 mmol) in DMF (30 mL) were added NaOH (1.12 g, 27.9 mmol) and NaI (139 mg, 930 μmol). The mixture was then stirred at 50 ° C for 2 h. After completion, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2×30 mL). The mixture was then adjusted to pH=6 with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine (2×30 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to give a residue. The product was purified by flash silica gel chromatography ( 40g The residue was purified by HPLC-MS/MS (HPLC-MS/MS, HPLC-MS/MS, HPLC-MS/MS, 500 μg/mL SilicaFlash Column, eluent 0 to 30% ethyl acetate/petroleum ether gradient, at 80 mL/min) to give the title compound (1.6 g, 65% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝12.39-12.11 (m, 1H), 8.24 (s, 1H), 7.78 (s, 1H), 4.11 (t, J＝6.8 Hz, 2H), 3.74 (s, 1H), 2.13 (dt, J＝2.4, 6.8 Hz, 2H), 1.80-1.70 (m, 2H), 1.47-1.37 (m, 2H), 1.34-1.14 (m, 10H).

[(1R,3S)-3-[1-tert-butyl-5-[(1-undec-10-ynylpyrazole-4-carbonyl)amino]pyrazol-3-yl] cyclopentyl [pentyl] N-isopropylcarbamate (Intermediate Z)

To a solution of 1-undec-10-ynylpyrazole-4-carboxylic acid (600 mg, 2.29 mmol, intermediate Y) and [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (588 mg, 1.91 mmol, intermediate U) in MeCN (6 mL) was added T ₃ P (3.64 g, 5.72 mmol, 50% solution in DMF) and DIEA (1.23 g, 9.53 mmol, 1.66 mL). The mixture was stirred at 60 °C for 12 h. Upon completion, the mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine (2×10 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to give a residue. The product was purified by flash silica gel chromatography ( 20g The residue was purified by Silica Flash Column, eluent 0 to 45% ethyl acetate/petroleum ether gradient at 80 mL/min) to give the title compound (530 mg, 41% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 553.4 (M+H) ⁺ .

1-(Non-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid (Intermediate AA)

Step 1 - 4-Methylbenzenesulfonate non-8-yn-1-yl ester. To a solution of non-8-yn-1-ol (5 g, 35.6 mmol, CAS# 10160-28-8) and 4-methylbenzenesulfonyl chloride (8.16 g, 42.7 mmol) in DCM (60 mL) was added TEA (10.8 g, 106 mmol) at 0°C. The mixture was then stirred at 0-20°C for 12 h. Upon completion, the mixture was quenched with sat. NaHCO ₃ (80 mL) and diluted with DCM (60 mL). The organic layer was washed with H ₂ O (60×3 mL) and brine (60×3 mL), then dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 10/1) to give the title compound (6.8 g, 62% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.77 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 4.00 (t, J = 6.4Hz, 2H), 2.43 (s, 3H), 2.13 (dt, J = 2.4, 7.2Hz, 2H), 1.92 (t, J = 2.4Hz, 1 H),1.66-1.58(m,2H),1.51-1.40(m,2H),1.36-1.19(m,6H).

Step 2 - Methyl 2-(non-8-yn-1-yl)-1H-pyrazole-5-carboxylate. Sodium hydride (978 mg, 28.5 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of methyl 1H-pyrazole-5-carboxylate (1.29 g, 10.1 mmol) in DMF (40 mL) at 0°C, and the mixture was then stirred at 0°C for 0.5 h. Subsequently, a solution of non-8-ynyl 4-methylbenzenesulfonate (3 g, 10.19 mmol) was added dropwise. The resulting mixture was stirred at 0-20°C for 12 h. The mixture was quenched with sat. NH ₄ Cl (40 mL), and then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (40 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by prep-HPLC (FA conditions, column: Phenomenex luna C18 250*50 mm*15 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 39%-69%, 25 min) to give the title compound (0.5 g, 19% yield) as a colorless oil ( ¹ H NMR (400 MHz, CDCl ₃ )δ＝7.48(d, J＝2.0 Hz, 1H), 6.83(d, J＝2.0 Hz, 1H), 4.62-4.52(m, 2H), 3.89(s, 3H), 2.18(dt, J＝2.4, 7.2 Hz, 2H), 1.94(t, J＝2.4 Hz, 1H), 1.84(quintet, J＝7.2 Hz, 2H), 1.57-1.48(m, 2H), 1.43-1.29(m, 7H)) and 1-non-8-ynylpyrazole-3-carboxylic acid methyl ester (1.3 g, 50% yield) ( ¹ H NMR (400MHz, chloroform-d) δ = 7.40 (d, J = 2.4Hz, 1H), 6.82 (d, J = 2.4Hz, 1H), 4.19 (t, J = 7.2Hz, 2H), 3.93 (s, 3H), 2.17 (dt, J = 2.4, 7.2Hz, 2H), 1.96-1.85 (m, 3H), 1.56 -1.46(m,2H),1.42-1.29(m,6H)).

Step 3 - 1-(Non-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid. To a solution of methyl 2-(non-8-yn-1-yl)-1H-pyrazole-5-carboxylate (0.5 g, 2.01 mmol) in THF (4 mL) was added a solution of LiOH.H ₂ O (337 mg, 8.05 mmol) in H ₂ O (1 mL). The mixture was stirred at 25 °C for 12 h. Upon completion, the solution was diluted with water (10 mL) and extracted with EtOAc (15 mL). The aqueous phase was adjusted to pH <4 by HCl (1 M) and then extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine (30 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (0.33 g, 63% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.54 (s, 1H), 6.98 (s, 1H), 4.59 (t, J=7.2 Hz, 2H), 2.18 (dt, J=2.4, 7.2 Hz, 2H), 1.96-1.82 (m, 4H), 1.52 (td, J=7.2, 14.4 Hz, 3H), 1.45-1.31 (m, 8H).

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-(non-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid (Amino)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate AB)

A solution of 1-(non-8-yn-1-yl)-1H-pyrazole-5-carboxylic acid (0.3 g, 1.28 mmol, intermediate AA), [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (434 mg, 1.41 mmol, intermediate U), T ₃ P (2.44 g, 3.84 mmol, 50% solution in DMF) and DIEA (330 mg, 2.56 mmol) in MeCN (4 mL) was stirred at 80 °C for 12 h. After completion, the mixture was diluted with EtOAc (10 mL) and quenched with sat. NH ₄ Cl (10 mL). The mixture was extracted with EtOAc (20 mL×3) and the organic layer was washed with brine (20 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (0.3 g, 36% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.55 (d, J=2.0 Hz, 1H), 7.47 (br s, 1H), 6.61 (br s, 1H), 6.30 (s, 1H), 5.16 (br s,1H),4.60(t,J＝7.3Hz,2H),3.87-3.77(m,1H),3.17-3.05(m,1H),2.53-2.42(m,1H),2.17(dt,J＝2.4,7.2Hz,2H),2.07-2.04(m,1H),1.94-1.84(m ,6H),1.65(s,9H),1.53-1.48(m,2H),1.44-1.30(m,7H),1.27(t,J＝7.2Hz,1H),1.15(dd,J＝2.4,6.4Hz,6H).

1-(Dodecan-11-yn-1-yl)-1H-pyrazole-3-carboxylic acid (Intermediate AC)

To a solution of methyl 1-dodec-11-ynylpyrazole-3-carboxylate (1.1 g, 3.79 mmol, intermediate AK) and LiOH.H ₂ O (635 mg, 15.1 mmol) in THF (12 mL) and H ₂ O (3 mL), the mixture was then stirred at 20° C. for 12 hr. Upon completion, the reaction mixture was quenched with H ₂ O 20 mL at 20° C., and then diluted with EtOAc 10 mL and extracted with EtOAc (20 mL×3). The aqueous phase was then adjusted to pH=3 to 4, and then extracted with EtOAc (20 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (1 g) as a yellow solid. This product was used in the next step without further purification. LC-MS (ESI ⁺ ) m/z 567.7 (M+H) ⁺ .

[(1R,3S)-3-[1-tert-butyl-5-[(1-dodec-11-ynylpyrazole-3-carbonyl)amino]pyrazol-3-yl] cyclopentyl [pentyl] N-isopropylcarbamate (Intermediate AD)

To a solution of 1-dodec-11-ynylpyrazole-3-carboxylic acid (200 mg, 723 μmol, Intermediate AC) and (1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (267 mg, 868 μmol, Intermediate U) in MeCN (2 mL) was added T ₃ P (1.38 g, 2.17 mmol, 50% solution in DMF) and DIEA (467.64 mg, 3.62 mmol). The mixture was stirred at 80° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (3 mL) at 25° C. and then diluted with EtOAc (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with sat. NaCl (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (250 mg, 61% yield) as an orange solid. LCMS: tR=0.840 min., (ES+) m/z (M+H)+=568.1.

1-(2-(2-(Prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (Intermediate AE)

Step 1 - 2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-prop-2-ynyloxyethoxy)ethanol (2 g, 13.8 mmol) in DCM (60 mL) was added TEA (7.02 g, 69.36 mmol) and DMAP (169 mg, 1.39 mmol) and 4-methylbenzenesulfonyl chloride (5.29 g, 27.7 mmol) at 20° C. under nitrogen atmosphere. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (60 mL) and extracted with dichloromethane (50 mL×2). The combined organic phases were washed with brine (2×40 mL), dried over sodium sulfate, filtered and the filtrate concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (3 g, 72% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.82 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.24-4.13 (m, 4H), 3.75-3.69 (m, 2H), 3.68-3.60 (m, 4H), 2.49-2.43 (m, 4H).

Step 2 - Methyl 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate. To a solution of methyl 1H-pyrazole-4-carboxylate (1.0 g, 8.0 mmol) and 2-(2-prop-2-ynyloxyethoxy)ethyl 4-methylbenzenesulfonate (2 g, 6.7 mmol) in DMF (40 mL) was added KI (111 mg, 670 μmol) and Cs ₂ CO ₃ (4.3 g, 13.4 mmol) at 0° C. under a stream of nitrogen. The reaction was then stirred at 70° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with brine (2×20 mL), dried over sodium sulfate, filtered and the filtrate concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:40) to give the title compound (1.5 g, 88% yield) as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.02 (s, 1H), 7.90 (s, 1H), 4.31 (t, J=5.12 Hz, 2H), 4.17 (d, J=2.0 Hz, 2H), 3.86-3.84 (m, 2H), 3.82 (s, 3H), 3.67-3.63 (m, 2H), 3.62-3.57 (m, 2H), 2.45 (t, J=2.12 Hz, 1H).

[0266] Step 3 - 1-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid. To a solution of methyl 1-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-4-carboxylate (1.5 g, 5.95 mmol) in THF (24 mL) and _H2O (6 mL) was added _LiOH.H2O (998 mg, 23.7 mmol) at 20°C under a stream of nitrogen. The reaction was then stirred at 40°C under nitrogen atmosphere for 15 h. Upon completion, the reaction was poured into ice water (20 mL) and acidified with 3N hydrochloric acid to pH = 3, then extracted with ethyl acetate (2 x 30 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and the filtrate was concentrated to give the title compound as a residue. ¹ H NMR (400MHz, CDCl ₃ ) δ = 8.03 (s, 1H), 7.90 (s, 1H), 4.28 (t, J = 5.12Hz, 2H), 4.11 (d, J = 2.4Hz, 2H), 3.80 (t, J = 5.12Hz, 2H), 3.62-3.50 (m, 4H), 2.38 (t, J = 2. 4Hz,1H).

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-prop-2-yn-1-yloxy)ethoxy (4-(2-(2-(4-(2-((2-((4-(2-( ...

To a solution of 1-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-4-carboxylic acid (668 mg, 2.8 mmol, Intermediate AE) and [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (0.4 g, 1.30 mmol, Intermediate U) in ACN (10 mL) was added T ₃ P (2.68 g, 4.21 mmol, 50% solution in DMF) and DIEA (906 mg, 7.01 mmol, 1.22 mL) at 20° C. under a stream of nitrogen. The reaction was then stirred at 60° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (15 mL) and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (2×10 mL), dried over sodium sulfate, filtered and the filtrate concentrated to give a residue. The residue was purified by prep-TLC (petroleum ether:ethyl acetate=0:1) to give the title compound (0.25 g, 33% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.23-7.56 (m, 2H), 6.19 (br s, 1H), 5.15 (br s, 1H), 4.77-4.60 (m, 1H), 4.33 (br d, J=4.2 Hz, 2H), 4.18 (d, J=2.4 Hz, 1H), 3.87 (br t,J＝4.92Hz,2H),3.83-3.72(m,1H),3.69-3.53(m,3H),3.26-2.99(m,1H),2.52-2.45(m,1H),2.44(t,J＝2.4Hz,1H),2.11-2.00(m,1H),1.99-1.74 (m,5H),1.63(s,9H),1.18-1.10(m,6H).

Benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate AG) and (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (intermediate AH)

Step 1-3, 3-dimethoxycyclopentanecarboxylic acid methyl ester. To a solution of 3-oxocyclopentanecarboxylic acid (42 g, 328 mmol, CAS#98-78-2) in MeOH (180 mL) was added trimethoxymethane (174 g, 1.64 mol, 180 mL) and TsOH.H ₂ O (12.5 g, 65.6 mmol). The mixture was stirred at 20° C. for 3 hr. Subsequently, Na ₂ CO ₃ (80 g) was added to the mixture, and the mixture was stirred at 20° C. for 11 hours. After completion, the mixture was filtered and the filtrate was concentrated in vacuo. Water (200 mL) was added to the mixture. The mixture was extracted with EtOAc (200 mL×3). The organic phase was washed with brine (200 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (55.2 g, 89% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 3.72-3.62 (m, 3H), 3.23-3.15 (m, 6H), 2.93-2.79 (m, 1H), 2.15-2.01 (m, 2H), 2.00-1.84 (m, 3H), 1.83-1.75 (m, 1H).

Step 2-3-(3,3-dimethoxycyclopentyl)-3-oxopropionitrile. At -65 ° C, n-BuLi solution (2.5M, 15.9mL) was added dropwise to a reactor containing THF (120mL). Subsequently, anhydrous MeCN (1.64g, 39.9mmol, 2.1mL) was added dropwise, slowly enough to maintain the internal temperature below -65 ° C. The mixture was stirred for another 1hr at -65 ° C. A solution of methyl 3,3-dimethoxycyclopentanecarboxylate (5g, 26.6mmol) in THF (40mL) was then added dropwise. After addition, the reaction mixture was stirred at -65 ° C for 2hr. After completion, the mixture was quenched with water (60mL), neutralized with saturated NH ₄ Cl aqueous solution to pH = 9 to 10 and extracted with ethyl acetate (60mL×3). The combined organic layers were washed with sat.aq NaCl (50 mL x 2), dried _over anhydrous _Na2SO4 , filtered, and concentrated in vacuo to give the title compound (3.9 g, 19.8 mmol, 74% yield) as a ^yellow oil.1H NMR (400 MHz, _CDCl3 ) δ = 3.53-3.50 (m, 2H), 3.21-3.18 (m, 7H), 2.08 (d, J = 8.4 Hz, 2H), 1.94-1.81 (m, 4H).

Step 3-2-tert-butyl-5-(3,3-dimethoxycyclopentyl)pyrazole-3-amine. To a solution of tert-butylhydrazine (2.88 g, 23.1 mmol, HCl) in EtOH (40 mL) was added NaOH (925 mg, 23.1 mmol) at 25 ° C. After addition, the mixture was stirred at 25 ° C for 0.5 hr, and then a solution of 3-(3,3-dimethoxycyclopentyl)-3-oxopropionitrile (3.8 g, 19.3 mmol) in EtOH (40 mL) was added dropwise. The resulting mixture was stirred at 75 ° C for 15.5 hr. After completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by flash silica gel chromatography (20 g Silica Flash Column, ethyl acetate/petroleum ether: 0 to 35%) to give the title compound as a yellow oil (3.7 g, 72% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ＝5.43(s, 1H), 5.48-5.35(m, 1H), 3.56-3.43(m, 1H), 3.49(br d, J＝1.2 Hz, 1H), 3.23(d, J＝4.0 Hz, 6H), 3.19-3.09(m, 1H), 2.27(m, 1H), 2.01-1.93(m, 1H), 1.88-1.69(m, 4H), 1.61(s, 9H).

Step 4-(1-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester. To a solution of 2-tert-butyl-5-(3,3-dimethoxycyclopentyl)pyrazol-3-amine (3.7 g, 13.8 mmol) in MeCN (50 mL) was added NaHCO ₃ (3.49 g, 41.5 mmol). After addition, the mixture was stirred at 25° C. for 0.5 h, and then CbzCl (3.54 g, 20.8 mmol, 2.95 mL) was added dropwise at 0° C. The resulting mixture was stirred at 25° C. for 15.5 h. Upon completion, the reaction mixture was quenched with H ₂ O (80 mL) and then diluted with ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The product was purified by flash silica gel chromatography (20 g The residue was purified by X-ray diffraction (HPLC) using DMF (4% 4-nitropropene) (M+H+ Silica Flash Column, ethyl acetate/petroleum ether: 0 to 35%) to give the title compound (1.12 g, 21% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 356.3 (M+H) ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ＝7.48-7.30 (m, 5H), 6.28 (s, 1H), 6.10 (s, 1H), 5.20 (s, 1H), 3.51-3.36 (m, 1H), 2.62-2.53 (m, 1H), 2.50-2.31 (m, 3H), 2.28-2.16 (m, 1H), 2.11-2.05 (m, 1H), 1.58 (s, 9H).

Step 5-(1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl N-[2-tert-butyl-5-(3,3-dimethoxycyclopentyl)pyrazol-3-yl]carbamate (1.12 g, 2.96 mmol) in acetone (10 mL) and H ₂ O (10 mL) was added TosOH (10.3 g, 59.8 mmol), and then the mixture was stirred at 25 °C for 14 h. After completion, the mixture was concentrated and diluted with water (5 mL) and EtOAc (5 mL), then extracted with EtOAc (5 mL×3). The combined organic layers were washed with sat. NaHCO ₃ (500 mL×3) and brine (5 mL×3) and dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (1.1 g) as a yellow solid. LC-MS (ESI ⁺ ) m/z 356.0 (M+H).

Step 6 - Benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate. To _a solution of benzyl (1-(tert-butyl)-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl)carbamate (1 g, 2.81 mmol) in THF (15 mL) was added _LiBHEt3 (1 M, 5.63 mL) dropwise at -65°C under N2. After addition, the mixture was stirred at -65°C for 2 hr. Upon completion, the reaction mixture was quenched with sat.aq _NaHCO3 (30 mL) at -40 to -30°C. Subsequently, hydrogen peroxide (30% aqueous solution, 5 g) was added dropwise to the mixture while maintaining the internal temperature at -10 to 0°C. The mixture was then stirred at 10°C for 1 hour. After completion, the solution was then extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with sat.aq _{Na 2} SO ₃ (2 x 20 mL) and sat.aq NaCl (30 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give a residue. The product was purified by flash silica gel chromatography (12 g The residue was purified by ^HPLC (HPLC-MS/MS) using a 4% HPLC-MS/MS/MS HPLC-MS/MS (5% HPLC-MS _/ MS ...

Step 7 - Benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate and benzyl (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate. The enantiomers of benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (700 mg, 1.96 mmol) were separated by chiral SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [0.1% NH3H2O MEOH]; B%: 20%-20%, 2.4; 180 min) to give benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (308 mg, 43% yield) as a white solid (LC-MS (ESI ⁺ ) m/z 358.2 (M+H) ⁺ ; SFC (first eluting enantiomer peak, 1.076 min); ¹ H NMR (400 MHz, DMSO-d ₆ )δ＝9.20-8.85(m,1H),7.50-7.18(m,5H),5.93(s,1H),5.12(s,2H),4.57(d,J＝4.0Hz,1H),4.29-4.10(m,1H),2.90(m,1H),2.32-2.12(m,1H),1.91-1.80(m,1H),1.78-1.67(m,2H),1.66-1.56(m,1H),1.56-1.51(m,1H),1.48(s,9H) and benzyl (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (308 mg, 43% yield) as a white solid.

3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate AI)

[0136] Step 1 - Methyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate. A solution of methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (1 g, 5.88 mmol, CAS# 1208081-25-7) and DIEA (987 mg, 7.64 mmol, 1.33 mL) in DCM (12 mL) was cooled to 0 °C. A solution of MsCl (1.08 g, 9.43 mmol, 730 μL) in DCM (3 mL) was then added dropwise. The mixture was stirred at 0 °C for 45 min and then at 20 °C for 1 h 15 min. Upon completion, the reaction mixture was quenched with saturated _NH4Cl (30 mL) and then extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to give the title compound (1.46 g, crude) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 6.96 (s, 1H) 5.24 (s, 2H) 4.19 (s, 3H) 3.90 (s, 3H) 3.01 (s, 3H).

Step 2 - 3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester. To a solution of 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylic acid methyl ester (1.46 g, 5.88 mmol) in MeOH (15 mL) was added NaOMe (635 mg, 11.8 mmol) at 20 ° C. The mixture was stirred at 70 ° C for 30 minutes. After completion, the reaction mixture was poured into 0.5N HCl (30 mL) with stirring. The pH of the mixture was adjusted to 8 with sodium bicarbonate and then extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated to give the product. The crude product was purified by silica gel column chromatography (PE/EA=50/1 to 8/1) to give the title compound (750 mg, 69% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 6.82 (s, 1H) 4.34 (s, 2H) 4.06 (s, 3H) 3.83 (s, 3H) 3.25 (s, 3H).

Step 3 - 3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid. To a solution of methyl 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (740 mg, 4.02 mmol) in THF (7.6 mL) was added water (2.5 mL) and lithium hydroxide monohydrate (337 mg, 8.04 mmol). The mixture was stirred at 20° C. for 16 hr. Upon completion, the pH of the mixed reactant was adjusted to 3-4 with aq. HCl (1 M) and then diluted with water 25 mL and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (423 mg, 62% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.23-3.26 (m, 3H) 4.04 (s, 3H) 4.32 (s, 2H) 6.75 (s, 1H) 13.12-13.51 (m, 1H).

1-(Dodecan-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid methyl ester (Intermediate AJ) and 1-(Dodecan-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid methyl ester 1H-pyrazole-3-carboxylic acid methyl ester (Intermediate AK)

Step 1 - 4-methylbenzenesulfonate. To a solution of dodecan-11-yn-1-ol (3 g, 16.5 mmol, CAS#18202-10-3) and 4-methylbenzenesulfonyl chloride (3.45 g, 18.1 mmol, CAS#98-59-9) in DCM (30 mL) was added TEA (5.00 g, 49.4 mmol) at 0°C, and then the mixture was stirred at 0-20°C for 12 h. Upon completion, the reaction mixture was quenched by the addition of _NH4Cl 50 mL at 20°C, and then diluted with EtOAc 20 mL and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 3/1) to give the title compound (3.6 g, 65% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ=7.78 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 4.00 (t, J=6.4 Hz, 2H), 2.73 (t, J=2.8 Hz, 1H), 2.42 (s, 3H), 2.13 (dt, J=2.4, 6.8 Hz, 2H), 1.53 (quintet, J=6.8 Hz, 2H), 1.46-1.37 (m, 2H), 1.36-1.27 (m, 2H), 1.24-1.13 (m, 10H).

Step 2 - 1-(Dodecan-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid methyl ester and 1-(Dodecan-11-yn-1-yl)-1H-pyrazole-3-carboxylic acid methyl ester. To a solution of 1H-pyrazole-5-carboxylic acid methyl ester (1.19 g, 9.45 mmol, CAS# 15366-34-4) and 4-methylbenzenesulfonic acid dodecan-11-ynyl ester (2.65 g, 7.88 mmol) in DMF (30 mL) were added KI (131 mg, 788 μmol) and Cs ₂ CO ₃ (5.13 g, 15.8 mmol), and then the mixture was stirred at 70° C. for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (30 mL) at 20° C., and then diluted with EtOAc 30 mL and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylate (1 g, 43.7% yield) as a white solid ( ₁ H NMR (400 MHz, DMSO-d6) δ=7.55 (d, J=2.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 4.47 (t, J=7.2 Hz, 2H), 3.82 (s, 3H), 2.72 (t, J=2.8 Hz, 1H), 2.13 (dt, J=2.4, 6.8 Hz, 2H), 1.72 (quintet, J=7.2 Hz, 2H), 1.47-1.37 (m, 2H), 1.36-1.29 (m, 2H), 1.22 (br s, 10H) and methyl 1-(dodec-11-yn-1-yl)-1H-pyrazole-3-carboxylate (1.1 g, 48% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝7.55 (d, J＝2.0 Hz, 1H), 6.87 (d, J＝2.0 Hz, 1H), 4.47 (t, J＝7.2 Hz, 2H), 3.82 (s, 3H), 2.72 (t, J＝2.8 Hz, 1H), 2.13 (dt, J＝2.8, 6.8 Hz, 2H), 1.72 (q, J＝7.1 Hz, 2H), 1.47-1.37 (m, 2H), 1.36-1.29 (m, 2H), 1.22 (br s, 10H).

1-(Dodecan-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid ( (Intermediate AL)

To a solution of methyl 2-dodec-11-ynylpyrazole-3-carboxylate (1 g, 3.44 mmol, intermediate AJ) and LiOH.H ₂ O (578 mg, 13.8 mmol) in THF (12 mL) and H ₂ O (4 mL), the mixture was then stirred at 20° C. for 12 hr. Upon completion, the reaction mixture was quenched with H ₂ O 20 mL at 20° C., and then diluted with EtOAc 10 mL and extracted with EtOAc (20 mL×3). The aqueous phase was then adjusted to pH=3 to 4, and then extracted with EtOAc (20 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (930 mg) as a yellow solid. ¹ HNMR (400MHz, DMSO-d6) δ = 13.95-11.71 (m, 1H), 7.50 (d, J = 2.0Hz, 1H), 6.80 (d, J = 2.0Hz, 1H), 4.47 (t, J = 7.2Hz, 2H), 2.71 (t, J = 2.4Hz, 1H), 2.12 (dt, J = 2. 4, 6.8Hz, 2H), 1.91 (s, 2H), 1.72 (quintet, J = 7.2Hz, 2H), 1.46-1.37 (m, 2H), 1.36-1.27 (m, 2H), 1.22 (br s, 9H)

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-(dodec-11-yn-1-yl)-1H-pyrazole-5- carboxamido )-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate AM)

To a solution of 1-(dodec-11-yn-1-yl)-1H-pyrazole-5-carboxylic acid (500 mg, 1.81 mmol, Intermediate AL) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (558 mg, 1.81 mmol, Intermediate U) in MeCN (10 mL) were added DIEA (1.17 g, 9.05 mmol) and T ₃ P (3.45 g, 5.43 mmol, 50% solution), and the mixture was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C., and then diluted with EtOAc (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 1/1) to give the title compound (300 mg, 529 μmol, 29% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 567.7 (M+H) ⁺ .

3-[4-(7-Aminoheptyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (Intermediate AN)

Step 1 - Hept-6-yn-1-yl methanesulfonate. To a stirred solution of hept-6-yn-1-ol (30.00 g, 267.5 mmol) in DCM (450.00 mL) at 0°C under nitrogen atmosphere was added TEA (92.68 mL, 668.6 mmol) and MsCl (45.95 _g , 401.1 mmol) portionwise. The resulting mixture was then stirred at rt under nitrogen atmosphere for 2 h. Upon completion, the mixture was diluted with water (250 mL). The resulting mixture was extracted with _CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (1×100 mL) and dried _over anhydrous _Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (50 g). ¹ H NMR (400MHz, CDCl ₃ ) δ4.28-4.24(m,2H),3.03(s,3H),2.27-2.22(m,2H),1.98(s,1H),1.84-1.77(m,2H),1.60-1.52(m,6H).

Step 2 - 7-azidohept-1-yne. To a stirred solution of hept-6-yn-1-yl methanesulfonate (50.00 g, 262.8 mmol) in DMF (500.0 mL) was added _NaN3 (25.63 g, 394.2 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 50 °C under nitrogen atmosphere overnight. Upon completion, the reaction mixture was diluted with water (1 L). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×100 mL) and then dried _over anhydrous _Na2SO4 . After filtration, the filtrate was concentrated under reduced pressure to give the title compound (36 g) as a pale oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 3.30 (t, J = 6.8 Hz, 2H), 2.23 (td, J = 6.8, 2.6 Hz, 2H), 1.97 (s, 1H), 1.72-1.41 (m, 6H).

[0266] Step 3-Hept-6-yn-1-amine hydrochloride. To a stirred solution of 7-azidohept-1-yne (36.00 g, 262.4 mmol) in THF (400 mL) and _H2O (40.00 mL) was added _PPh3 (103.24 g, 393.6 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 60°C under nitrogen atmosphere for 2 h. Upon completion, the solution was concentrated under reduced pressure and diluted with DCM (300 mL). The mixture was acidified to pH 1 with HCl (2M aq.) and the aqueous layer was extracted with DCM (3 x 100 mL). The aqueous layer was concentrated under reduced pressure to give the title compound (38 g, 98% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.09 (broad peak, 3H), 2.82-2.67 (m, 3H), 2.18-2.14 (m, 2H), 1.61-1.53 (m, 2H), 1.49-1.35 (m, 4H). LC/MS (ESI, m/z): [(M+1)] ⁺ =112.2.

[0136] Step 4: tert-butyl N-(hept-6-yn-1-yl)carbamate. To a stirred solution of hept-6-yn-1-amine hydrochloride (28.00 g, 190.5 mmol) in DCM (500.00 mL) was added TEA (144.8 mL, 952.4 mmol) and Boc ₂ O (62.28 g, 285.7 mmol) portionwise at rt under nitrogen atmosphere. The resulting mixture was stirred overnight at rt under nitrogen atmosphere. Upon completion, the reaction mixture was diluted with water (1 L) and extracted with CH ₂ Cl ₂ (3×200 mL). The combined organic layers were washed with brine (2×300 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1) to give the title compound (40 g, 99% yield) as a light yellow solid. ¹ H NMR (400MHz, chloroform-d) δ 4.56-4.52 (m, 1H), 3.16-3.12 (m, 2H), 2.21 (td, J = 7.0, 2.6Hz, 2H), 1.96 (t, J = 2.7Hz, 1H), 1.62-1.49 (m, 6H), 1.46 (s, 9H). LC/MS (ESI, m/z): [(M+1-56)] ⁺ =156.2.

Step 5 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]hept-6-yn-1-yl]carbamate. To a stirred mixture of 3-(4-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, intermediate H) and tert-butyl N-(hept-6-yn-1-yl)carbamate (10.00 g, 47.32 mmol) in DMA (50.00 mL) and TEA (25.00 mL) were added CuI (450.55 mg, 2.366 mmol) and Pd( _PPh3 ) ₄ (2.73 g, 2.34 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 3 h. After completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with brine (3×50 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residual product was purified by reverse phase fast (column: Spherical C18, 20 to 40 μm, 330 g; mobile phase A: water (0.05% FA), mobile phase B: ACN; flow rate: 45 mL/min; gradient (B%): 5% to 5%, 8 min; 40% to 70%, 30 min; 70% to 95%; 0 min; 95%, 5 min; detector: 254 nm; Rt: 22.3 min.) to give the title compound (6 g, 54% yield) as a light yellow solid. ¹ HNMR(400MHz,DMSO-d ₆ )δ11.12(s,1H),7.11(d,J＝7.7Hz,1H),7.06(d,J＝7.6Hz,1H),6.99(t,J＝7.8Hz,1H),6.81(t,J＝5.9Hz,1H),5.39(dd,J＝12.6,5.4Hz,1H),3.65(s,3H),2.99-2.79(m,3H),2.78-2.56(m,2H),2.51-2.47(m,2H),2.06-1.98(m,1H),1.56(d,J＝6.9Hz,2H),1.43-1.39(m,4H),1.36(s,9H)。 LC/MS (ESI, m/z): [(M+1)] ⁺ =469.3.

Step 6 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]heptyl]carbamate. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]heptyl-6-yn-1-yl]carbamate (6.50 g, 13.9 mmol) in MeOH (500 mL) was added portionwise Pd/C (2.21 g, 20.8 mmol) at rt under a nitrogen atmosphere. The resulting mixture was stirred overnight at rt under a hydrogen atmosphere. Upon completion, the resulting mixture was filtered and the filter cake was washed with MeOH (5×100 mL). The filtrate was concentrated under reduced pressure to give the title compound (6 g, 92% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12(s,1H),6.97-6.93(m,2H),6.88-6.85(m,1H),6.77(t,J＝5.8Hz,1H),5.37(dd,J＝12.6,5.4Hz,1H),3.55(s,3H),2.95-2 .86(m,5H),2.80-2.57(m,2H),2.04-1.96(m,1H),1.563-1.56(m,2H),1.41-1.22(m,17H). LC/MS (ESI, m/z): [(M+1)] ⁺ =473.3.

Step 7 - 3-(4-(7-aminoheptyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]heptyl]carbamate (6.00 g, 12.9 mmol) in DCM (50.00 mL) was added dropwise a solution of HCl(g) in 1,4-dioxane (20 mL) at rt under an atmosphere of air. The resulting mixture was stirred at rt under a nitrogen atmosphere for 2 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was triturated with _Et2O to afford the title compound (4.5 g, 90% yield) as a white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 7.85 (broad peak, 3H), 7.01-6.92 (m, 2H), 6.88-6.84 (m, 1H), 5.38 (dd, J = 12.7, 5.4Hz, 1H), 3.56 (s, 3H), 2.97-2.83 (m, 3 H),2.80-2.63(m,4H),2.05-1.91(m,1H),1.64-1.51(m,4H),1.43-1.24(m,6H). LC/MS (ESI, m/z): [(M+1)] ⁺ =373.3.

3-((Hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate AO)

Step 1 - Hept-6-yn-1-yl 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylate. Sodium hydride (264 mg, 6.61 mmol, 60% dispersion in mineral oil) was added to a solution of hept-6-yn-1-ol (618 mg, 5.51 mmol, CAS# 63478-76-2) in THF (8 mL) at 0°C, and the resulting mixture was stirred at 0°C for 0.5 h. Then a solution of methyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate (800 mg, 2.76 mmol, synthesized via step 1-2 of Intermediate AI) in THF (2 mL) was added, and the mixture was stirred at 0°C for 2 h. Upon completion, the reaction mixture was quenched with 20 mL of _H2O at 20°C and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 1/1) to give the title compound (600 mg, 51.84% yield) as a brown oil. LC-MS (ESI ⁺ ) m/z 345.2 (M+H) ⁺ .

[0266] Step 2 - 3-((Hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid. To a solution of hept-6-yn-1-yl 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylate (600 mg, 1.74 mmol) in _H2O (1 mL) and THF (4 mL) was added _LiOH.H2O (292 mg, 6.97 mmol), and then the mixture was stirred at 20 °C for 3 h. After completion, the reaction mixture was filtered and diluted with _H2O (5 mL), then extracted with EtOAc (8 mL x 3). The aqueous phase was then adjusted to pH = 3 to 4, and extracted with EtOAc (8 mL x 3). The combined organic layers were washed with brine (5 mL x 3), dried _{over Na2SO4} , filtered and concentrated in vacuo to give the title compound (400 mg) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ＝13.35-13.25(m,1H),6.80-6.66(m,1H),4.38-4.30(m,2H),3.38(q,J＝6.0Hz,3H),3.29(brs,3H),2.74-2.71(m,1H),2.14(d t,J＝2.4,6.8Hz,4H),1.44-1.34(m,9H).

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(3-((hept-6-yn-1-yloxy)methyl)-1- Methyl-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate AP)

To a solution of 3-((hept-6-yn-1-yloxy)methyl)-1-methyl-1H-pyrazole-5-carboxylic acid (243 mg, 973 μmol, Intermediate AO), (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (200 mg, 648 μmol, Intermediate U) in pyridine (2 mL) was added POCl ₃ (199 mg, 1.3 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. Upon completion, the reaction mixture was quenched by the addition of glacial NaHCO _{3 3} mL at 20° C. and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (5 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was analyzed by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate＝0:1) to give the title compound (70 mg, 20% yield) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ Cl) δ 6.67-6.59 (m, 1H), 6.32 (s, 1H), 5.21-5.11 (m, 1H), 5.00 (br dd,J＝2.8,4.4Hz,1H),4.52(s,2H),4.19(s,3H),3.86-3.75(m,1H),3.54(t,J＝6.8Hz,2H),3.21-3.12(m,1H),2.93-2.84(m,2H),2.56-2.42(m,2H),2 .21(dt,J＝2.4,6.8Hz,3H),2.10-2.03(m,2H),1.94(t,J＝2.4Hz,1H),1.92-1.86(m,2H),1.66(s,8H),1.63-1.46(m,6H),1.19-1.11(m,6H).

tert-Butyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate (Intermediate AQ)

Step 1-5-tert-butyl 3-ethyl 1-methyl-1H-pyrazole-3,5-dicarboxylate. A solution of ethyl (E)-ethyl 2-(2-methylhydrazono)acetate (10 g, 76.8 mmol, MDL# MFCD31391018), tert-butyl acrylate (14.8 g, 115 mmol), I ₂ (3.9 g, 15.4 mmol, CAS# 1663-39-4), and benzoyl peroxide (55.8 g, 230 mmol) in ACN (180 mL) was stirred at 80° C. for 6 h. After completion, the mixture was quenched with Na ₂ SO ₃ (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with brine (200 mL×3), dried over Na ₂ SO ₄ , and then concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (6.5 g, 33% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ=7.15 (s, 1H), 4.28 (q, J=7.2 Hz, 3H), 4.13 (s, 3H), 3.32 (s, 2H), 1.54 (s, 9H), 1.29 (t, J=7.2 Hz, 4H).

Step 2-tert-butyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate. To a solution of 5-tert-butyl 3-ethyl 1-methyl-1H-pyrazole-3,5-dicarboxylate (6.5 g, 25.6 mmol) in THF (60 mL) was slowly added LiBH ₄ (3 g, 138 mmol) at 0° C., and the mixture was then stirred at the same temperature for 1 h. After completion, the reaction mixture was quenched by dropwise addition of H ₂ O (60 mL) at 20° C., and the solution was subsequently extracted with EtOAc (60 mL×3). The combined organic layers were washed with brine (60 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 3/1) to give the title compound (2.5 g, 46% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 213.3(M+H) ⁺ .

Step 3 - tert-Butyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate. To a solution of tert-butyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (2.4 g, 11.3 mmol) and DIEA (4.39 g, 33.9 mmol) in DCM (30 mL) was added methanesulfonyl chloride (1.94 g, 16.9 mmol) at 0°C, and then the mixture was stirred at 0°C for ₁ h. After completion, the reaction mixture was quenched with _NH4Cl (sat.aq, 20 mL) at 20°C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (1.5 g, 46% yield) as a yellow gum. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.91 (s, 1H), 5.19 (s, 2H), 4.06 (s, 3H), 3.22 (s, 3H), 1.54 (s, 9H).

1-Methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid (Intermediate AR)

Step 1 - Non-8-yn-1-yl 1-methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylate. Sodium hydride (248 mg, 6.20 mmol, 60% dispersion in mineral oil) was added portionwise to a solution of non-8-yn-1-ol (724 mg, 5.17 mmol, CAS# 10160-28-8) in THF (8 mL) at 0° C., and the mixture was then stirred at 0° C. for 0.5 h. Subsequently, a solution of tert-butyl 1-methyl-3-(((methylsulfonyl)oxy)methyl)-1H-pyrazole-5-carboxylate (750 mg, 2.58 mmol, Intermediate AQ) in THF (4 mL) was added dropwise, and the resulting mixture was stirred at 0° C. for 2 hr. After completion, the reaction mixture was quenched with _H2O (10 mL) at 20°C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give the title compound (600 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 401.3 (M+H) ⁺ .

Step 2 - 1-Methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid. LiOH.H ₂ O (251 mg, 5.99 mmol) was added in one portion to a solution of 1-methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid non-8-yn-1-yl ester (600 mg, 1.50 mmol2) in H ₂ O (2 mL) and THF (8 mL), and the resulting mixture was then stirred at 25 °C for 12 h. After completion, the reaction mixture was filtered and diluted with H ₂ O (5 mL), and extracted with EtOAc (8 mL×3). The aqueous phase was then adjusted to pH=3 to 4, and extracted with EtOAc (8 mL×3). The combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (400 mg) as a brown oil. LC-MS(ESI ⁺ )m/z 279.1(M+H) ⁺ .

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-methyl-3-((non-8-yn-1-yloxy)methyl) (1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate AS)

_POCl3 (441 mg, 2.87 mmol) was added dropwise to a solution of 1-methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid (400 mg, 1.44 mmol, Intermediate AR) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (488 mg, 1.58 mmol, Intermediate U) in pyridine (4 mL) at 0°C, and then the resulting mixture was stirred at 0°C for 2 h. Upon completion, the reaction mixture was quenched with glacial _H2O (5 mL) at 20°C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (210 mg, 26% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 6.99 (s, 1H), 6.91 (br d, J=5.6 Hz, 1H), 6.02 (s, 1H), 5.01-4.96 (m, 1H), 4.39 (s, 2H), 4.02 (s, 3H), 3.45-3.40 (m, 2H), 2.72 (t, J=2.8 Hz, 1H), 2.39 (br dd, J=8.0, 14.4 Hz, 2H), 2.13 (dt, J=2.8, 6.8 Hz, 2H), 1.96 (br d,J＝7.2Hz,1H),1.86(td,J＝3.2,5.6Hz,1H),1.74-1.67(m,2H),1.56(s,1H),1.51(s,9H),1.43-1.27(m,8H),1.03(s,3H),1.01(s,3H).

2-(1H-pyrazol-4-yl)acetate tert-butyl ester (AT )

Step 1- (2-(tert-butoxy)-2-oxoethyl)zinc (II) bromide. Zn (40.6 g, 622 mmol, powder) was slowly added to a solution of HCl (1 M, 232 mL). The mixture was stirred at 20 ° C for 5 min. The mixture was filtered and the solid was washed with acetone (100 mL×2). The solid was then dried in vacuo. A mixture of Zn (27 g) and TMSCl (2.23 g, 20.5 mmol) in anhydrous THF (120 mL) was warmed to 60 ° C. A solution of tert-butyl 2-bromoacetate (40 g, 205 mmol, CAS#5292-43-3) in THF (270 mL) was then added dropwise to the reaction mixture. The mixture was stirred at 60 ° C for 0.5 hours. The mixture was filtered and the filtrate was used in the next step without further purification.

Step ₂ - tert-Butyl 2-(1H-pyrazol-4-yl)acetate. To a mixture of tert-butyl 4-bromopyrazole-1-carboxylate (25 g, 101 mmol), _Pd2 (dba) ₃ (4 g, 4.37 mmol), XPhos (4.5 g, 9.44 mmol) was added a solution of bromo-(2-tert-butoxy-2-oxo-ethyl)zinc (52.7 g, 202 mmol) in THF (380 mL) in one portion under N2. The mixture was stirred at 70°C under _N2 for 12 hours. The mixture was concentrated in vacuo and purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 10/1, 2/1) to give the title compound (5 g, 27.4 mmol, 27% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.57 (s, 2H), 3.47 (s, 2H), 1.48 (s, 9H).

Isopropyl 2-(1-(hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate (Intermediate AU)

[0136] Step 1: Hept-6-yn-1-yl 4-methylbenzenesulfonate. To a solution of hept-6-yn-1-ol (1.00 g, 8.92 mmol, CAS# 63478-76-2) and TEA (2.71 g, 26.75 mmol ₎ in DCM (12 mL) was slowly added TosCl (1.87 g, 9.81 mmol) at 0°C. The mixture was stirred at 20°C for 2 h. Upon completion, the mixture was diluted with DCM (20 mL) and then washed with water (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 20/1) to give the title compound (2.00 g, 84% yield) as a colorless oil. ¹ HNMR (400MHz, CDCl ₃ ) δ = 7.80 (d, J = 8.0Hz, 2H), 7.35 (d, J = 8.0Hz, 2H), 4.04 (t, J = 6.4Hz, 2H), 2.46 (s, 3H), 2.15 (dt, J ₁ = 6.8Hz, J ₂ = 2.4Hz, 2H), 1.93 (t, J =2.4Hz,1H),1.74-1.62(m,2H),1.50-1.38(m,4H).

Step 2 - Isopropyl 2-(1-(hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate. To a solution of tert-butyl 2-(1H-pyrazol-4-yl)acetate (400 mg, 2.20 mmol, intermediate AT) in DMSO (6 mL) was added KOH (370 mg, 6.59 mmol) and 4-methylbenzenesulfonic acid hept-6-ynyl ester (760 mg, 2.85 mmol) in one portion, followed by NaI (33 mg, 0.22 mmol). The mixture was stirred at 50 °C for 2 h. After completion, the residue was introduced into ice water (10 mL). The aqueous phase was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous _{Na2SO4 ,} filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (1000 mesh silica gel, petroleum ether/ethyl acetate = 30/1 to 20/1) to give the title compound (350 mg, 48% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 277.1 (M+H) ⁺ .

2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole (4-oxazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetic acid (Intermediate AV)

Step 1 - tert-Butyl 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate. To a mixture of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (245 mg, 0.72 mmol, intermediate H), tert-butyl 2-(1-hept-6-ynylpyrazol-4-yl)acetate (200 mg, 0.61 mmol, intermediate AU), Pd( _PPh3 ) _2Cl2 (51 mg, 0.07 mmol) and CuI (14 mg, 0.07 mmol) in DMF ₍ 8 mL) was added TEA (110 mg, 1.09 mmol) in one portion. The mixture was stirred at 60°C under _N2 for 3 h. Upon completion, the mixture was concentrated in vacuo and purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 11.5min) and then lyophilized to give the title compound (40 mg, 10% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 534.3 (M+H) ⁺ .

Step 2 - tert-Butyl 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetate. To a solution of tert-butyl 2-[1-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-benzoimidazol-4-yl]hept-6-ynyl]pyrazol-4-yl]acetate (40 mg, 0.07 mmol) in THF (3 mL) was added Pd/C (20 mg, 10 wt%) in one portion. The mixture was stirred at 20° C. under H ₂ (15 psi) for 2 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (39 mg, 97% yield) as a colorless oil. LC-MS(ESI ⁺ )m/z 538.4(M+H) ⁺ .

Step 3 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetic acid. To a solution of tert-butyl 2-[1-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-benzoimidazol-4-yl]heptyl]pyrazol-4-yl]acetate (39 mg, 0.07 mmol) in DCM (1.5 mL) was slowly added TFA (462 mg, 4.05 mmol) at 0°C. The mixture was stirred at 20°C for 3 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (34 mg, 97% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 482.3 (M+H) ⁺ .

3-(1-(Non-8-yn-1-yl)-1H-pyrazol-4-yl)acetic acid (Intermediate AW)

Step 1 - tert-Butyl 2-(1-(non-8-yn-1-yl)-1H-pyrazol-4-yl)acetate. To a solution of tert-butyl 2-(1H-pyrazol-4-yl)acetate (667 mg, 3.66 mmol, Intermediate AT) and non-8-yn-1-yl methanesulfonate (1.2 g, 5.50 mmol, synthesized via Step 1 of Intermediate O) in DMSO (14 mL) was added KOH (616 mg, 11.0 mmol) and KI (60.8 mg, 366 μmol) at 20° C. under a nitrogen stream. The reaction was then stirred at 50° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (20 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phases were washed with brine (4×10 mL) and dried over sodium sulfate. The solution was then filtered and the filtrate was concentrated to give a residue. The reactant was purified by silica gel column chromatography (ethyl acetate = 100: 1 to 100: 30) to give the title compound (0.8 g, 71.7% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.33 (s, 1H), 7.19 (s, 1H), 4.00 (t, J = 7.1 Hz, 2H), 3.32 (s, 2H), 2.10 (dt, J = 2.6, 7.1 Hz, 2H), 1.87-1.84 (m, 1H), 1.78 (td, J = 7.1, 14.2 Hz, 2H), 1.41-1.22 (m, 18H).

Step 2-3-(1-(non-8-yn-1-yl)-1H-pyrazol-4-yl)acetic acid. To a solution of tert-butyl 2-(1-(non-8-yn-1-yl)-1H-pyrazol-4-yl)acetate (400 mg, 1.31 mmol) in DCM (5 mL) was added TFA (1.54 g, 13.5 mmol) at 20° C. under a stream of nitrogen. The reactants were then stirred at 20° C. under a nitrogen atmosphere for 1 h. Upon completion, the reactants were poured into ice water (8 mL) and extracted with dichloromethane (2×10 mL). The combined organic phases were washed with brine (2×10 mL) and dried over sodium sulfate. The filtrate was then filtered to give and concentrated to give the title compound (370 mg) as a colorless oil. ¹ H NMR (400MHz, CDCl3) δ7.6 (s, 1H), 7.47 (s, 1H), 4.19 (t, J = 7.2Hz, 2H), 3.59 (s, 2H), 2.21-2.15 (m, 2H), 1.98-1.92 (m, 1H), 1.87 (quintet, J = 7.2Hz, 2H), 1.4 6-1.30(m,8H).

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(2-(1-(non-8-yn-1-yl)-1H-pyrazole-4- (2-(4-( ...

To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (400 mg, 1.30 mmol, Intermediate U) and 2-(1-(non-8-yn-1-yl)-1H-pyrazol-4-yl)acetic acid (611 mg, 2.46 mmol, Intermediate AW) in ACN (4 mL) was added T ₃ P (2.48 g, 3.89 mmol, 50% solution in DMF) and DIEA (838 mg, 6.48 mmol) at 20° C. under a stream of nitrogen. The reaction was then stirred at 20° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine (2×5 mL) and dried over sodium sulfate. It was then filtered to obtain the filtrate and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (0.5 g, 928 μmol, 72% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl 3 ) δ=7.51 (s, 1H), 7.42 (s, 1H), 7.31 (s, 1H), 6.34 (s, 1H), 5.14 (br s, 1H), 4.64-4.51 (m, 1H), 4.13 (tt, J=3.5, 7.2 Hz, 3H), 3.81 (br d,J＝6.6Hz,1H),3.64(s,2H),3.07(quintet,J＝8.5Hz,1H),2.44(td,J＝6.9,13.8Hz,1H),2.24-2.13(m,2H),2.05(s,1H),2.04-1.98(m,1H),1.94(t,J＝2 .6Hz,1H),1.92-1.73(m,6H),1.58-1.47(m,3H),1.43(s,8H),1.37-1.30(m,4H),1.18-1.12(m,6H).

2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole (4-(2-((2-oxazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetic acid (Intermediate AY)

Step 1: tert-Butyl 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-5-yl)hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate. To tert-butyl 2-(1-hept-6-ynylpyrazol-4-yl)acetate (100 mg, 0.30 mmol, intermediate AU), 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (122 mg, 0.36 mmol, intermediate J), Pd(PPh ₃ ) ₂ Cl ₂ (25 mg, 0.04 mmol) and CuI (7 mg, 0.04 mmol) in a mixture of THF (1.5 mL) and ACN (1.5 mL) were added TEA (55 mg, 0.54 mmol) in one portion. The mixture was stirred at 60 °C under _N2 for 3 h. After completion, the mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 40%-70%, 11.5 min) and lyophilized to give the title compound (70 mg, 36% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 534.3 (M+H) ⁺ .

Step 2 - tert-Butyl 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetate. To a solution of tert-butyl 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)hept-6-yn-1-yl)-1H-pyrazol-4-yl)acetate (70 mg, 0.13 mmol) in THF (3 mL) was added Pd/C (20 mg, 10 wt%) in one portion. The mixture was stirred at 20° C. under _H atmosphere (15 psi) for 12 h. After completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless oil (70 mg, 99% yield). LC-MS (ESI+) m/z 538.4 (M+H) ⁺ .

Step 3 - 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetic acid . To a solution of tert-butyl 2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetate (70 mg, 0.13 mmol) in DCM (2 mL) was slowly added TFA (770 mg, 6.75 mmol) at 0°C. The mixture was stirred at 20°C for 3 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (62 mg, 99% yield) as a yellow oil. LC-MS(ESI ⁺ )m/z 482.3(M+H) ⁺ .

1-(7-Bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (Intermediate AZ)

Step 1 - 7-bromo-3-iodo-imidazo[1,2-a]pyridine. To a solution of 7-bromoimidazo[1,2-a]pyridine (9.50 g, 48.2 mmol, CAS#808744-34-5) in DMF (150 mL) was added NIS (13.02 g, 57.86 mmol) at 25 °C. The mixture was then stirred at 100 °C for 1 hr. Upon completion, the reaction mixture was poured into 400 mL of water and extracted with EtOAc (200 mL x 2). The organic layer was washed with water (200 mL), saturated brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product. The product was purified by flash silica gel chromatography ( 120g The crude product was purified by silica flash column, eluent 0 to 5% ethyl acetate/petroleum ether gradient, at 150 mL/min) to afford the compound as a dark brown solid (11.6 g, 74% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.00 (d, J=7.2 Hz, 1H), 7.82 (d, J=1.2 Hz, 1H), 7.67 (s, 1H), 7.04 (dd, J=2.0, 7.3 Hz, 1H).

Step 2 - 1-(7-Bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione. To _a solution of 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (4.00 g, 17.0 mmol, intermediate CR) and 7-bromo-3-iodo-imidazo[1,2-a]pyridine (6.62 g, 20.4 mmol) in 1,4-dioxane (80.0 mL) in _{dioxane was added Cs2CO3 (} 11.1 g, 34.1 mmol), CuI (650 mg, 3.42 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (485 mg, 3.42 mmol) at 25 °C under N2. The mixture was then stirred at 80 ° C for 16 hr. After completion, the reaction mixture was poured into 200 mL of water and extracted with EtOAc (100 mL × 2). The combined organic layer was washed with water (200 mL), saturated brine (200 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product. The crude product was purified by silica gel chromatography, eluted with petroleum ether/ethyl acetate = 10/1 to 0/1 to give the title compound (2.00 g, 27% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 429.0 (M+H) ⁺ .

Step 3-1-(7-bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione. A solution of 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (0.90 g, 2.10 mmol) in TFA (10 mL) and TfOH (0.2 mL) was stirred at 60° C. for 4 hours. After completion, the mixture was concentrated to give a residue, which was then adjusted to pH 6-7 by TEA at 0° C. The mixture was concentrated to give a residue. The residue was suspended in EtOAc (30 mL) and stirred for 0.5 hr. The suspension was filtered and the filter cake was concentrated in vacuo to give the title compound (485 mg, 73% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.67 (s, 1H), 8.31 (d, J = 7.2Hz, 1H), 7.92 (s, 1H), 7.58 (s, 1H), 7.14 (d, J = 6.4Hz, 1H), 3.80 (t, J = 6.4Hz, 2H), 2.82 (t, J = 6.0Hz, 2H ). LC-MS(ESI ⁺ )m/z 309.0(M+H) ⁺ .

2-[[5-Bromo-2-(2-methyl-4-sulfamoyl-phenylamino)pyrimidin-4-yl]amino]-6-fluoro-benzamide (Medium Intermediate BA)

Step 1 - 2-((5-bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide. To a solution of 5-bromo-2,4-dichloro-pyrimidine (5.00 g, 21.9 mmol, CAS#36082-50-5) and 2-amino-6-fluoro-benzamide (3.72 g, 24.1 mmol, CAS#115463-59-9) in i-PrOH (50 mL) was added DIPEA (5.67 g, 43.8 mmol) in one portion. The resulting mixture was stirred at 90 °C for 24 h to give a yellow solution. Upon completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo to give the title compound (0.83 g, 72% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.64 (s, 1H), 8.57 (s, 1H), 8.23-8.14 (m, 2H), 8.09 (d, J = 8.4Hz, 1H), 7.60-7.54 (m, 1H), 7.15-7.09 (m, 1H); LC/MS (ESI, m/z): [M +1] ⁺ =346.7.

[0266] Step 2 - 2-((5-bromo-2-((2-methyl-4-sulfamoylphenyl)amino)pyrimidin-4-yl)amino)-6-fluorobenzamide. To a solution of 2-((5-bromo-2-chloropyrimidin-4-yl)amino)-6-fluorobenzamide (200 mg, 0.57 mmol) and 4-amino-3-methyl-benzenesulfonamide (108 mg, 0.57 mmol, CAS# 53297-70-4) in 2-butanol (3 mL) was added TFA (770 mg, 6.75 mmol) in one portion. The resulting mixture was stirred at 100 °C for 24 h. Upon completion, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The crude product was triturated with EtOH at 25 °C for 30 min to afford the title compound (55 mg, 18% yield) as a purple solid. ¹ H NMR (400MHz, CDCl ₃ ) δ=6.30-6.27(m,1H),6.29-6.27(m,1H),6.22(s,1H),4.46-4.44(m,2H),4.19-4.17(m,1H),4.14-4.12(m,3H),3.9-3.96(m,2 H), 3.93-3.92 (m, 3H), 2.26 (s, 2H); LC/MS (ESI, m/z): [M+1] ⁺ = 469.9.

4-((5-bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl Chlorine (Intermediate BB)

A solution of 2-[[5-bromo-2-(2-methyl-4-sulfamoyl-phenylamino)pyrimidin-4-yl]amino]-6-fluoro-benzamide (100 mg, 0.20 mmol) in ClSO ₃ H (0.20 mmol, 2 mL) was stirred at 80 °C for 2 h. Upon completion, the reaction mixture was poured into ice. The mixture was then extracted with CH ₂ Cl ₂ (20 mL). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (100 mg, 71% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 515.9 (M+H) ⁺ .

1-(Non-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid (Intermediate BC)

Step 1 - 4-Methylbenzenesulfonate Non-8-yn-1-yl ester. To a mixture of non-8-yn-1-ol (1.50 g, 10.7 mmol, CAS# 10160-28-8) in DCM (20 mL) at 0°C was added TosCl (2.65 g, 13.90 mmol) and TEA (3.25 g, 32.10 mmol), then the mixture was stirred at 25°C for 2 h. The reaction mixture was partitioned between DCM (10 mL) and _H2O (5 mL). The organic phase was separated, _dried over _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 40g The residue was purified by HPLC-MS/MS (HPLC-MS/MS, HPLC-MS/MS, eluent: 0 to 13% ethyl acetate/petroleum ether gradient, 60 mL/min) to give the title compound as a colorless oil (2.80 g, 67% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.78 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.00 (t, J=6.4 Hz, 2H), 2.69 (t, J=2.8 Hz, 1H), 2.41 (s, 3H), 2.10 (dt, J ₁ =7.2 Hz, J ₂ =2.4 Hz, 2H), 1.58-1.50 (m, 2H), 1.39-1.32 (m, 2H), 1.29-1.13 (m, 6H).

Step 2 - tert-Butyl 1-(non-8-yn-1-yl)-1H-pyrazole-4-carboxylate. To a mixture of non-8-ynyl 4-methylbenzenesulfonate (2.80 g, 7.13 mmol), tert-butyl 1H-pyrazole-4-carboxylate (1.00 g, 5.95 mmol, CAS# 611239-23-7) and NaOH (713 mg, 17.8 mmol) in DMF (20 mL) was added NaI (89 mg, 0.60 mmol) in one portion, and then the mixture was stirred at 50 °C for 1 h. The reaction mixture was partitioned between EtOAc (10 mL) and H ₂ O (10 mL). The organic phase was separated, washed with brine (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 40g The residue was purified by HPLC-MS/MS (ESI ^{+) (HPLC-MS/MS) using a Silica Flash Column, eluent 0 to 22% ethyl acetate/petroleum ether gradient at 50 mL/min) to give the title compound as a colorless oil (1.30 g, 75% yield). LC-MS (ESI+} ) m/z 292.2 (M+H) ⁺ .

Step 3-1-(non-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of tert-butyl 1-non-8-ynylpyrazole-4-carboxylate (1.30 g, 4.48 mmol) in DCM (9 mL) was added TFA (4.62 g, 40.5 mmol), and the mixture was subsequently stirred at 25 ° C for 12 h. After completion, the reaction mixture was filtered. The crude product was purified by reverse phase flash (FA conditions) to give the title compound (950 mg, 91% yield) as a light yellow solid. LC-MS (ESI ⁺ ) m / z 235.4 (M + H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 13.00-11.35 (m, 1H), 8.24 (s, 1H), 7.78 (s, 1H), 4.11 (t, J = 6.8Hz, 2H), 2.72 (t, J = 2.8Hz, 1H), 2.13 (dt, J ₁ = 6.8Hz, J ₂ = 2.8Hz ,2H),1.79-1.73(m,2H),1.43-1.37(m,2H),1.33-1.25(m,4H),1.21-1.16(m,2H).

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-(non-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid (Amino)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BD)

To a mixture of 1-(non-8-yn-1-yl)-1H-pyrazole-4-carboxylic acid (137 mg, 0.58 mmol, Intermediate BC) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 0.49 mmol, Intermediate U) in MeCN (2 mL) was added T ₃ P (464 mg, 1.46 mmol, 50% solution in DMF) and DIPEA (94 mg, 0.73 mmol) in one portion and then the mixture was stirred at 50° C. for 48 h. Upon completion, the reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography ( 25g The residue was purified by Silica Flash Column, eluent 0 to 50% ethyl acetate/petroleum ether gradient at 50 mL/min) to give the title compound (150 mg, 56% yield) as a white gum. LC-MS (ESI ⁺ ) m/z 525.2 (M+H) ⁺ .

1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (intermediate BE)

Step 1 - 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethanol (10 g, 53.1 mmol, CAS# 208827-90-1) and TosCl (12.1 g, 63.7 mmol) in DCM (110 mL) were added TEA (16.1 g, 159 mmol) and DMAP (259 mg, 2.13 mmol) in one portion. The mixture was then stirred at 0-20 °C for 12 h. Upon completion, the mixture was poured into ice water (120 mL) and extracted with DCM (2 x 120 mL). The combined organic phases were washed with brine (2 x 120 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The product was purified by flash silica gel chromatography ( 120g The residue was purified by HPLC-MS/MS (HPLC-MS/MS, HPLC-MS/MS, HPLC-MS/MS, 5 min). SilicaFlash Column, eluent 0 to 10% ethyl acetate/petroleum ether gradient, at 80 mL/min) to give the title compound (19.8 g, 50.8 mmol, 96% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.79 (br d, J=2.4 Hz, 2H), 7.47 (br s, 2H), 4.12 (br s, 4H), 3.62-3.42 (m, 10H), 2.42 (br s, 3H), 2.03-1.94 (m, 1H).

Step 2 - Methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate and methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylate. To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (2 g, 5.84 mmol) and methyl 1H-pyrazole-5-carboxylate (736 mg, 5.84 mmol) in DMF (20 mL) were added KI (96.9 mg, 584 μmol) and Cs ₂ CO ₃ (1.90 g, 5.84 mmol) in one portion. The resulting mixture was stirred at 20-70° C. for 12 h. After completion, the mixture was poured into ice water (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phases were washed with brine (2×30 mL) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography ( 20g The residue was purified by HPLC-MS/MS (HPLC-MS/MS/MS/ESI+) with 5% ethyl acetate in 4% iodine (5% NaOH) and 1% pyrazole-5-carboxylic acid methyl ester (680 mg, 39% yield) as a yellow oil (LC-MS (ESI+) m/z 297.2 (M+H) ⁺ ). The residue was purified by HPLC-MS/MS/ESI+) with 5% ethyl acetate in 4% iodine (5% NaOH) as a yellow oil (LC-MS (ESI ⁺ ) m/z 297.2 (M+H)+). The residue was purified by HPLC-MS/MS/ESI+) with 5% ethyl acetate in 4% iodine (5% NaOH) as a yellow oil (LC-MS (ESI ⁺ ) m/z 297.2 (M+H) ⁺ ).

Step 3 - 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid. To a solution of methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (326 mg, 1.10 mmol) in THF (3 mL) and H ₂ O (1 mL) at 0° C. was added LiOH.H ₂ O (184 mg, 4.40 mmol). The mixture was then stirred at 0-20° C. for 2 h. Upon completion, the mixture was poured into ice water (4 mL) and extracted with ethyl acetate (2×4 mL). The aqueous phase was acidified to pH=2 with aqueous HCl and extracted with ethyl acetate (2×4 mL). The combined organic phases were washed with brine (2×4 mL) and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil (280 mg). LC-MS (ESI ⁺ ) m/z 283.3 (M+H) ⁺ .

Isopropylcarbamic acid (1R, 3S)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy) (Ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BF)

[0136] To a solution of 2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid (280 mg, 991.88 μmol, Intermediate BE) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (367 mg, 1.19 mmol, Intermediate U) in ACN (5 mL) was added T ₃ P (1.89 g, 2.98 mmol, 50% solution in DMF) and DIEA (641 mg, 4.96 mmol) in one portion. The resulting mixture was stirred at 20-60° C. for 12 h. Upon completion, the mixture was poured into ice water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phases were washed with brine (2×10 mL) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/1) to give the title compound (530 mg, 890 μmol, 90% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 573.3 (M+H) ⁺ .

1-(2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxylic acid (Intermediate BG)

Step 1 - tert-Butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (2 g, 8.68 mmol, CAS# 77279-24-4) and TEA (1.32 g, 13.0 mmol, 1.81 mL) in DCM (30 mL) was slowly added dropwise a solution of MsCl (1.19 g, 10.4 mmol) in DCM (10 mL) at 0°C under a stream of nitrogen. The reactants were then stirred at 20°C under a nitrogen atmosphere for 2 h. Upon completion, the mixture was poured into saturated aqueous NaHCO ₃ solution (50 mL) at 0°C and extracted with dichloromethane (40 mL×2). The combined organic phases were washed with brine (40 mL×2) and dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give the title compound (2.8 g) as a yellow oil.

Step 2 - tert-Butyl 4-(2-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-(2-((methylsulfonyl)oxy)ethyl)piperazine-1-carboxylate (2.8 g, 9.08 mmol) and methyl 1H-pyrazole-5-carboxylate (1.15 g, 9.08 mmol, CAS# 15366-34-4) in DMF (40 mL) was added KI (15 mg, 907 μmol) and Cs ₂ CO ₃ (14.8 g, 45.4 mmol) at 20° C. under nitrogen flow. The reaction was then stirred at 70° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (40 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with brine (30 mL×2) and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC [column: YMC Triart C18 250*50mm*7μm; mobile phase: [water (0.05% ammonium hydroxide v/v)-ACN]; B%: 38%-68%, 22min] to give the title compound (0.55g, 18% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ=7.42 (d, J=2.0 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 4.64 (t, J=6.8 Hz, 2H), 3.8 (s, 3H), 3.31 (br s, 4H), 2.72 (br t, J=6.4 Hz, 2H), 2.39 (br s, 4H), 1.38 (s, 9H).

Step 3 - 1-(2-(4-(tert-Butyloxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxylic acid. To a solution of methyl tert-butyl 4-(2-(5-(methoxycarbonyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (0.16 g, 579 μmol) in THF (2 mL), MeOH (1 mL) and H ₂ O (1 mL) was added LiOH.H ₂ O (97.2 mg, 2.32 mmol) at 0° C. under a stream of nitrogen. The reaction was then stirred at 20° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 1%-25%, 11.5min) and lyophilized to give the title compound (15mg, 98.7% yield) as a colorless oil. ^1H NMR (400MHz, DMSO- _d6 ) δ7.45 (d, J=2.0Hz, 1H), 6.67 (d, J=.0Hz, 1H), 4.62 (t, J=6.4Hz, 2H), 3.23 (d, J=2.4Hz, 2H), 2.89 (s, 3H), 2.77-2.70 (m, 5H), 2.43 (br s, 3H).

Isopropylcarbamate (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(prop-2-yn-1-yl)piperazine-1-yl) (1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BH)

Step 1-tert-Butyl 4-(2-(5-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate. To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (1.15 g, 3.73 mmol, Intermediate U) and 1-(2-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxylic acid (1.1 g, 3.39 mmol, Intermediate BG) in ACN (22 mL) was added _T3 at 0°C under a nitrogen stream. P (6.47 g, 10.17 mmol, 50% solution) and DIEA (2.19 g, 16.96 mmol). The reactant was then stirred at 20-60 ° C under a nitrogen atmosphere for 10 h. After completion, the reactant was poured into ice water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (30 mL × 2) and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1 to 0: 100) to give the title compound (1.1 g, 1.79 mmol, 52.7% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl3) δ = 7.54 (d, J = 2.0Hz, 1H), 6.67 (br s, 1H), 6.20 (s, 1H), 5.13 (br s, 1H), 4.74 (t, J = 6.4Hz, 2H), 4.68-4.54 (m, 1H), 3.49-3.27 (m, 4H), 3 .16-3.02(m,1H),2.92-2.79(m,2H),2.54-2.37(m,5H),1.89-1.73(m,4H),1.66-1.58(m,8H),1.49-1.39(m,11H),1.19-1.09(m,6H).

Step 2-(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A solution of tert-butyl 4-(2-(5-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethyl)piperazine-1-carboxylate (0.6 g, 975 μmol) in HCl/dioxane (4M, 10 mL) was stirred at 20 °C for 1 h. After completion, the reaction was concentrated to give the title compound (502 mg, crude) as a colorless oil. LC-MS(ESI ⁺ )m/z 645.2(M+H) ⁺ .

Step 3-(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (502 mg, 975 μmol) in ACN (10 mL) was added _K2CO3 (1.35 g, 9.75 mmol) and 3-bromoprop-1-yne (116 mg, 780 μmol, 80% solution) at ₀ °C under a stream of nitrogen. The reactant was then stirred at 20 ° C under a nitrogen atmosphere for 10 h. After completion, the reactant was poured into ice water (15 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1 to 100: 70) to give the title compound (0.45 g, 814 μmol, 83.4% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl3) δ = 7.56 (s, 1H), 6.71-6.59 (m, 1H), 6.27 (s, 1H), 5.26-5.08 (m, 1H), 4.91-4.69 (m, 2H), 4.63-4.49 (m, 1H), 3.87-3.69 (m, 3H), 3. 40-3.22(m,2H),3.17-2.41(m,13H),2.02-1.74(m,7H),1.66(s,9H),1.64-1.61(m,3H),1.44(s,3H),1.15(dd,J＝2.0,6.4Hz,8H).

1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (intermediate Physical BI)

Step 1 - Methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (1.21 g, 3.55 mmol, synthesized via step 1 of intermediate BE), KI (58.9 mg, 355 μmol) and Cs ₂ CO ₃ (3.47 g, 10.6 mmol) in DMF (13 mL) was added methyl 1H-pyrazole-4-carboxylate (537 mg, 4.26 mmol, CAS# 181997-36-4) at 25° C. and then the mixture was stirred at 70° C. for 2 h. Upon completion, the mixture was quenched with water (30 mL) and diluted with EtOAc (20 mL×3). The organic layer was washed with brine (20 mL x 3) and dried over _Na2SO4 , then concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl _acetate = 5/1 to 0/1) to give the title compound (1.10 g, 94% yield) as a colorless solid. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.02 (s, 1H), 7.91 (s, 1H), 4.31 (t, J = 5.2 Hz, 2H), 4.20 (d, J = 2.4 Hz, 2H), 3.86 (t, J = 5.2 Hz, 3H), 3.83 (s, 3H), 3.72-3.63 (m, 5H), 3.62-3.58 (m, 4H). LC-MS (ESI ⁺ ) m/z 297.2 (M+H) ⁺ .

Step 2 - 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid. A mixture of methyl 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate (1.00 g, 3.37 mmol) and LiOH.H ₂ O (566 mg, 13.5 mmol) in THF (12 mL) and H ₂ O (4 mL) was stirred at 25 °C for 12 h. After completion, the mixture was quenched with sat. _{NH 4} Cl (20 mL), diluted with EtOAc (20 mL), and extracted with water (20 mL). The aqueous layer was then acidified to pH <4 with HCl (1 N, 4 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL x 3), dried over _Na2SO4 , and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = _5/1 to 0/1) to give the title compound (300 mg, 28%) as a colorless oil. ^1H NMR (400 MHz, _CDCl3 ) δ = 8.11 (s, 1H), 7.97 (s, 1H), 4.35 (t, J = 5.2 Hz, 2H), 4.21 (d, J = 2.4 Hz, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.72-3.69 (m, 2H), 3.67-3.64 (m, 2H), 2.44 (t, J = 2.4 Hz, 1H), 2.12 (s, 1H). LC-MS(ESI ⁺ )m/z 283.1(M+H) ⁺ .

Isopropylcarbamic acid (1S,3R)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy) (Ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BJ)

A solution of 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (200 mg, 708 μmol, intermediate BI), (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (240 mg, 779 μmol, intermediate U), DIEA (183 mg, 1.42 mmol) and T ₃ P (1.35 g, 2.13 mmol, 50% solution in DMF) in MeCN (8 mL) was stirred at 80 °C for 12 h. After completion, the mixture was quenched with sat. NH ₄ Cl (10 mL), diluted with EtOAc (20 mL), and extracted with EtOAc (15 mL×3). The organic layer was washed with brine (15 mL x 3), dried over _Na2SO4 , and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl _acetate = 0/1) to give the title compound (70.0 mg, 14.6% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 573.3 (M+H) ⁺ .

1-(3,6,9,12-Tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid (Intermediate BK)

Step 1 - 3,6,9,12-tetraoxapentadeca-14-yn-1-yl 4-methylbenzenesulfonate. To a solution of 3,6,9,12-tetraoxapentadeca-14-yn-1-ol (2 g, 8.61 mmol, CAS#87450-10-0) and 4-methylbenzene-1-sulfonyl chloride (1.81 g, 9.47 mmol) in DCM (20 mL) was added TEA (2.61 g, 25.8 mmol) in one portion. The resulting mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched with _H2O (20 mL) at 20 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 0/1) to give the title compound (2.5 g, 75% yield) as a yellow gum. LC-MS (ESI ⁺ ) m/z 387.1 (M+H) ⁺ .

Step 2 - 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid methyl ester. A mixture of 1H-pyrazole-4-carboxylic acid methyl ester (196 mg, 1.55 mmol, CAS# 181997-36-4), 4-methylbenzenesulfonic acid 3,6,9,12-tetraoxapentadeca-14-yn-1-yl ester (0.5 g, 1.29 mmol), _Cs2CO3 (843 mg, 2.59 mmol), KI (21.5 mg, 129 μmol) in DMF (5 _mL ) was stirred at 70°C under _N2 atmosphere for 1 h. After completion, the reaction mixture was quenched with _H2O (10 mL) at 20°C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 1/1) to give the title compound (410 mg, 93% yield) as a yellow gum. ^1H NMR (400 MHz, DMSO-d6) δ = 8.31 (s, 1H), 7.86 (s, 1H), 4.30 (t, J = 5.2 Hz, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.78 (t, J = 5.2 Hz, 2H), 3.73 (s, 3H), 3.56-3.39 (m, 13H).

Step 3 - 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid. A solution of methyl 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-4-carboxylate (400 mg, 1.18 mmol) and LiOH.H ₂ O (197 mg, 4.70 mmol) in THF (3 mL) and H ₂ O (1 mL) was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (10 mL×3). The aqueous phase was then adjusted to pH=3 to 4 and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (20 mL x 2), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (250 mg, 65 _% yield) as a yellow solid. ^1H NMR (400 MHz, DMSO-d6) δ = 12.32 (br s, 1H), 8.21 (s, 1H), 7.79 (s, 1H), 4.29 (t, J = 5.2 Hz, 2H), 4.13 (d, J = 2.4 Hz, 2H), 3.77 (t, J = 5.4 Hz, 2H), 3.55-3.39 (m, 13H).

Isopropylcarbamic acid (1R,3S)-3-(5-(1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyridine 1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BL)

To a solution of 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-4-carboxylic acid (250 mg, 766 μmol, Intermediate BK) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (283 mg, 919 μmol, Intermediate U) in MeCN (6 mL) were added DIEA (495 mg, 3.83 mmol) and T ₃ P (1.46 g, 2.30 mmol, 50% solution in DMF) in one portion, and then the resulting mixture was stirred at 60° C. for 6 h. Upon completion, the reaction mixture was quenched with H ₂ O (6 mL) at 20° C. and extracted with EtOAc (6 mL×3). The combined organic layers were washed with brine (10 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC ( _SiO2 , ethyl acetate:petroleum ether = 0:1) to give the title compound (153 mg, 32% yield) as a colorless gum. LC-MS (ESI ⁺ ) m/z 617.8 (M+H) ⁺ .

1-(7-Chloroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate BM)

[0136] Step 1 - 4-Bromo-7-chloroisoquinoline. To a solution of 7-chloroisoquinoline (5.00 g, 30.5 mmol, CAS#34784-06-0) in DCE (50 mL) was added PhI(OAc) ₂ (14.7 g, 45.8 mmol) and KBr (18.1 g, 152 mmol) and the mixture was stirred at 50 °C for 16 h. After completion, the mixture was poured into water (100 mL) and extracted with EA (300 mL). The organic layer was washed with brine (2 x 100 mL), _dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The mixture was purified by silica gel column to give the title compound (5.50 g, 65% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 9.13 (s, 1H), 8.74 (s, 1H), 8.13 (d, J = 9.2 Hz, 1H), 7.99 ( d, J = 2.0 Hz, 1H), 7.77 ( dd, J = 2.0, 9.2 Hz, 1H).

Step 2 - 1-(7-Chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione. To a solution of 4-bromo-7-chloroisoquinoline (2.00 g, 8.25 mmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.93 g, 8.25 mmol, intermediate CS) in DMF (20 mL) were added (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (234 mg, 1.65 mmol), CuI (314 mg, 1.65 mmol) and _K2CO3 (3.42 g, 24.7 mmol). The mixture was then stirred at 100 °C under _N2 for 16 _h . Upon completion, the reaction solution was diluted with water (100 mL) and then extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and vacuum filtered. The mixture was purified by reverse phase flash: (C18, 10% to 40% MeCN in _H2O , 0.1% FA in _H2O ) to give the title compound (200 mg, 5% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.31 (s, 1H), 8.60 (s, 1H), 8.39 (d, J = 2.0Hz, 1H), 8.00 (d, J = 9.2Hz, 1H), 7.83 (dd, J = 2.0, 8.8Hz, 1H), 7.25 (d, J = 8.8Hz, 2H), 6.90- 6.86(m,2H),4.83(s,2H),4.00-3.94(m,1H),3.79-3.76(m,1H),3.73(s,3H),3.19-3.11(m,1H),2.99-2.92(m,1H).

Step 3 - 1-(7-Chloroisoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione. 1-(7-Chloroisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 126 μmol) was added in TFA (0.5 mL) and TfOH (0.01 mL) and the mixture was stirred at 60° C. for 2 hours. After completion, the reaction solution was diluted with water (5 mL) and then extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was further purified by prep-HPLC (column: [Phenomenex luna C18, 150mm*25mm*10μm]; mobile phase: (water (0.225% FA)-MeCN, MeCN%: 8%-38%); 11 min) to give the title compound (5.18 mg, 14% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.56 (s, 1H), 9.31 (s, 1H), 8.59 (s, 1H), 8.38 (d, J = 2.0Hz, 1H), 8.06 (d, J = 9.2Hz, 1H), 7.84 (dd, J = 2.4, 8.8Hz, 1H), 4.00-3.93 ( m,1H),3.75-3.69(m,1H),3.02-2.94(m,1H),2.78-2.71(m,1H). LC-MS(ESI ⁺ )m/z 275.9(M+H) ⁺ .

1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (Intermediate BN)

Step 1 - 8-Bromo-3-iodoimidazo[1,2-a]pyridine. To a solution of 8-bromoimidazo[1,2-a]pyridine (5.00 g, 25.3 mmol, CAS#850349-02-9) in CH ₃ CN (30 mL) was added NIS (5.71 g, 25.3 mmol) as intermediate CS at 25° C. The mixture was stirred at 25° C. for 0.5 hr. Upon completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column to afford the title compound (7.30 g, 89% yield) as a light green solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J=6.8 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.00 (t, J=7.2 Hz, 1H).

Step 2 - 1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)dione. A mixture of 8-bromo-3-iodo-imidazo[1,2-a]pyridine (500 mg, 1.55 mmol) and 3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (362 mg, 1.55 mmol, intermediate CS), CuI (58.9 mg, 309 μmol), Cs ₂ CO ₃ (1.01 g, 3.10 mmol), and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (44.0 mg, 309 μmol) in dioxane (10 mL) was stirred at 60 °C under N ₂ for 6 hours. After completion, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash (120 g Flash Column, Welch Ultimate XB_C18, 20-40 μm; 120A, 5% to 35% MeCN in H ₂ O, 0.5% FA in H ₂ O) and further purified by prep-HPLC (column: Waters xbridge, 150 mm*25 mm*10 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-MeCN]; B%: 22%-52%, 10 min) to give the title compound (200 mg, 10% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.35(dd,J＝0.8,6.8Hz,1H),7.69-7.67(m,1H),7.67(s,1H),7.24(d,J＝7.6Hz,2H),6.91(t,J＝7.2Hz,1H),6.87-6.84(m,2H),4. 81(s,2H),3.84(t,J＝6.4Hz,2H),3.72(s,3H),3.02(s,2H).

Step 3-1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione. A solution of 1-(8-bromoimidazo[1,2-a]pyridin-3-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (50.0 mg, 116 μmol) in TFA (0.5 mL) and TfOH (0.01 mL) was stirred at 70° C. for 2.5 hours. After completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Waters xbridge, 150 mm*25 mm*10 μm, water (10 mM NH ₄ HCO ₃ )-MeCN, 1% to 30% MeCN/H ₂ O, 11 min) and further purified by prep-HPLC (column: Phenomenex Luna C18, 150 mm*25 mm*10 μm; mobile phase: [water (0.225% FA)-MeCN]; MeCN%: 0%-20%, 11 min) to give the title compound (3.19 mg, 77% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.70 (s, 1H), 8.38 (d, J = 6.0Hz, 1H), 7.67-7.65 (m, 2H), 6.91 (t, J = 6.8Hz, 1H), 3.81 (t, J = 6.8Hz, 2H), 2.84 (t, J = 5.2Hz, 2H); LC-MS ( ESI ⁺ )m/z 308.9(M+H) ⁺ .

1-(8-Chloro-4-isoquinolyl)hexahydropyrimidine-2,4-dione (Intermediate BO)

Step 1 - 4-Bromo-8-chloro-isoquinoline. To a solution of 8-chloroisoquinoline (5.00 g, 30.5 mmol, CAS #34784-07-1) in AcOH (50 mL) was added NBS (7.07 g, 39.7 mmol), and the reaction mixture was then stirred at 50 °C for 40 min. Upon completion, the reaction mixture was diluted with water (100 mL) and then extracted with EA (3 x 80 mL). The combined organic layers were basified with NaHCO ₃ until pH = 6-7, and then the mixture was extracted with EA (2 x 60 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA = 100: 1 to PE:EA = 50: 1, PE:EA = 10: 1, P1:R _f = 0.74) to give the title compound (1.00 g, 37% yield) as a yellow solid. ¹ HNMR (400MHz, CDCl ₃ ) δ9.56 (s, 1H), 8.78 (s, 1H), 8.10-8.03 (m, 1H), 7.73-7.64 (m, 2H). LC-MS(ESI ⁺ )m/z 241.9(M+H) ⁺ .

Step 2 - 1-(8-Chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione. To a solution of 4-bromo-8-chloro-isoquinoline (100 mg, 412 μmol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (96.6 mg, 412.37 μmol, intermediate CR) in DMF (1 mL) were added CuI (7.85 mg, 41.2 μmol), (1S,2S)-N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (5.87 mg, 41.2 μmol) and K ₃ PO ₄ (175 mg, 824 μmol), and then the mixture was stirred at 110° C. for 8 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was diluted with water (50 mL) and extracted with EA (5 x 30 mL). The combined organic _layers were then dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (15 mg, 3.06% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.89-9.56 (br s, 1H), 8.59 (br s, 1H), 7.73-7.68 (m, 1H), 7.64 (t, J = 8.0Hz, 1H), 7.60-7.55 (m, 1H), 7.43 (d, J = 8.4Hz, 2H), 6.85 ( d,J＝8.4Hz,2H),5.00(s,2H),3.95-3.86(m,1H),3.80(s,3H),3.78-3.69(m,1H),3.07-2.99(m,2H); LC-MS(ESI ⁺ )m/z 396.1(M+H) ⁺ .

Step 3 - 1-(8-chloro-4-isoquinolyl)hexahydropyrimidine-2,4-dione. To a solution of 1-(8-chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (40.0 mg, 101 μmol) in TFA (0.49 mL) and TfOH (0.01 mL) was added and the mixture was then stirred at 60° C. for 2 hours. Upon completion, the mixture was concentrated to give a residue and purified by prep-HPLC (0.1% FA) to give the title compound (3 mg, 10.77% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.59 (s, 1H), 9.56 (s, 1H), 8.71 (s, 1H), 8.03 (d, J = 8.4Hz, 1H), 7.92-7.87 (m, 1H), 7.85-7.78 (m, 1H), 4.00-3.93 (m, 1H), 3.7 5-3.69(m 1H),3.03-2.95(m,1H),2.79-2.72(m,1H). LC-MS(ESI ⁺ )m/z 276.0(M+H) ⁺ .

3-(3-methyl-4-(3-(3-(methylamino)propoxy)propyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole oxazol-1-yl)piperidine-2,6-dione (Intermediate BP)

Step 1 - tert-Butyl N-methyl-N-[3-(prop-2-yn-1-yloxy)propyl]carbamate. To a stirred solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (25.00 g, 132.1 mmol) in DMF (200.0 mL) was added NaH (4.76 g, 198 mmol) portionwise at 0°C under nitrogen atmosphere. The above mixture was stirred at 0°C under nitrogen atmosphere for 30 min. Then propargyl bromide (23.57 g, 198.132 mmol, 1.50 equiv) was added dropwise to the mixture at 0°C. The resulting mixture was stirred for another 16 h at rt. After completion, the reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The resulting solution was purified on a silica gel column chromatography eluting with PE/EA (30:1) to give the title compound (47.7 g, 74%) as a yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.15 (d, J = 2.4 Hz, 2H), 3.54 (t, J = 6.3 Hz, 2H), 3.31 (t, J = 7.0 Hz, 2H), 2.87 (s, 3H), 2.43 (t, J = 2.4 Hz, 1H), 1.86-1.80 (m, 2H), 1.47 (s, 9H). LC/MS (ESI, m/z): [(M+1)] ⁺ = 228.2.

Step 2 - tert-Butyl N-(3-[2-[1-(2,6-dioxopiperidin-3-yl)-2-oxo-3H-1,3-benzodiazol-4-methylene]ethoxy]propyl)-N-methylcarbamate. To a stirred solution of tert-butyl N-methyl-N-[3-(prop-2-yn-1-yloxy)propyl]carbamate (16.50 g, 72.59 mmol) and 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (24.5 g, 72.59 mmol, intermediate H) in DMSO (140 mL) was added Pd(PPh ₃ ) ₄ dropwise at rt under nitrogen atmosphere. (8.39 g, 7.26 mmol) and CuI (392 mg, 7.26 mmol) and TEA (70 mL). The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 h. After completion, the mixture was cooled to rt. The product was purified by reverse phase flash (column: Spherical C18, 20 to 40 μm, 330 g; mobile phase A: water (10 mmol/LAcOH), mobile phase B: ACN; flow rate: 80 mL/min; gradient (B%): 52% to 72%, 20 min; detector: 254/220 nm), collecting the desired elution fraction at 62% B) and concentrated under reduced pressure to give the title compound (9.22 g, 80% yield) as a dark yellow foam. ¹ H NMR (400MHz, chloroform-d) δ8.20(s,1H),7.19(dd,J＝7.9,1.0Hz,1H),7.01(t,J＝7.9Hz,1H),6.78(dd,J＝8.0,1.1Hz,1H),5.22(dd,J＝12.5,5.3Hz,1H),4.42(s,2 H),3.79(s,3H),3.62(t,J＝6.3Hz,2H),3.34(t,J＝7.1Hz,2H),3.03-2.92(m,1H),2.89(s,3H),2.87-2.68(m,2H),2.33-2.20(m,1H),1.92-1.81(m, 2H),1.47(s,9H). LC/MS(ESI,m/z):[(M+1)] ⁺ =485.3.

Step 3 - tert-Butyl N-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]propoxy]propyl)-N-methylcarbamate. Pd/C was added to a mixture of N-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propyl]-N-methylcarbamate (8.00 g) in THF (200 mL) at rt. The reaction mixture was purged with nitrogen 3 times and stirred at rt under _H atmosphere for ⁵ h. Upon completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to afford the title compound (7.96 g, 88% yield) as a white solid. NMR (400MHz, chloroform-d) δ8.40(s,1H),7.00(t,J＝7.8Hz,1H),6.92(d,J＝7.7Hz,1H),6.69(d,J＝7.8Hz,1H),5.24(dd,J＝12.5,5.3Hz,1H),3.70(s,3H),3.50-3.44 (m,4H ),3.34-3.29(m,2H),3.05-3.01(m,2H),3.00-2.91(m,1H),2.88(s,3H),2.85-2.70(m,2H),2.25-2.20(m,1H),1.97-1.90(m,2H),1.86-1.80(m,2 H),1.48(s,9H). LC/MS (ESI, m/z): [(M+1)] ⁺ =489.3.

Step 4-3-(3-methyl-4-[3-[3-(methylamino)propoxy]propyl]-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione hydrochloride. To a stirred mixture of tert-butyl N-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-4-yl]propoxy]propyl)-N-methylcarbamate (8.50 g) in EA (200 mL) was added a solution of HCl (gas) in 1,4-dioxane (100 mL) in portions at rt under a nitrogen atmosphere. The resulting mixture was stirred for 4 h at rt under a nitrogen atmosphere. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by wet grinding with EA (100 mL) to give the title compound (7.34 g, 96% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 8.89 (broad peak, 2H), 7.00-6.96 (m, 2H), 6.90-6.86 (m, 1H), 5.39 (dd, J = 12.6, 5.4Hz, 1H), 3.57 (s, 3H), 3.49-3.43 (m, 5H),2.98-2.86(m,5H),2.77-2.57(m,2H),2.52-2.48(m,2H),2.05-1.95(m,1H),1.94-1.80(m,4H). LC/MS (ESI, m/z): [(M+1)] ⁺ =389.3.

1-1-(2-(2-(Benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (Intermediate BQ)

Step 1 - 2-(2-(Benzyloxy)ethoxy)ethyl 4-methylbenzenesulfonate. To a solution of 2-(2-(Benzyloxy)ethoxy)ethanol (10 g, 51.0 mmol, CAS#2050-25-1) and 4-methylbenzene-1-sulfonyl chloride (11.7 g, 61.2 mmol, CAS#98-59-9) in DCM (100 mL) was added TEA (15.5 g, 152 mmol) in one portion. The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (100 mL) at 20 °C and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The product was purified by flash silica gel chromatography ( 80g The residue was purified by Silica Flash Column, eluent 0 to 100% ethyl acetate/petroleum ether gradient at 100 mL/min) to give the title compound (15.3 g, 86% yield) as a colorless gum. ¹ H NMR (400 MHz, CD3Cl) δ 7.80 (d, J=8.4 Hz, 2H), 7.38-7.27 (m, 7H), 4.54 (s, 2H), 4.31-4.13 (m, 2H), 3.75-3.66 (m, 2H), 3.64-3.55 (m, 4H), 2.43 (s, 3H).

Step 2 - Methyl 1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylate. To a solution of 2-(2-(benzyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (5 g, 14.3 mmol) and methyl 1H-pyrazole-4-carboxylate (2.16 g, 17.1 mmol, CAS# 181997-36-4) in DMF (50 mL) were added Cs ₂ CO ₃ (9.3 g, 28.5 mmol) and KI (237 mg, 1.43 mmol) in one portion. The mixture was stirred at 70 °C for 1 h. Upon completion, the reaction mixture was quenched with H ₂ O (50 mL) at 20 °C and extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (50 mL×4), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (4.3 g, 99% yield) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d6) δ=8.32 (s, 1H), 7.88 (s, 1H), 7.40-7.21 (m, 5H), 4.43 (s, 2H), 4.32 (t, J=5.2 Hz, 2H), 3.79 (t, J=5.2 Hz, 2H), 3.72 (s, 3H), 3.59-3.47 (m, 4H).

Step 3-1-1-(2-(2-(Benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid. To a solution of 1H-pyrazole-4-carboxylic acid methyl ester (2 g, 6.57 mmol) in THF (6 mL) and H ₂ O (3 mL) was added LiOH.H ₂ O (1.10 g, 26.3 mmol) in one portion, and the resulting mixture was then stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (10 mL×3). The aqueous phase was then adjusted to pH=3 to 4 and extracted with EtOAc (10 mL×3). The organic layer was washed with brine (10 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (1.6 g, 84% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 12.31 (br s, 1H), 8.23 (s, 1H), 7.80 (s, 1H), 7.47-7.13 (m, 5H), 4.44 (s, 2H), 4.30 (t, J = 5.2Hz, 2H), 3.79 (t, J = 5.2Hz, 2H), 3.63- 3.45(m,4H).

2-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentanesulfonate (1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethoxy)ethyl ester (Intermediate BR)

Step 1-(1R,3S)-3-(5-(1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (0.5 g, 1.72 mmol, intermediate BQ) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (531 mg, 1.72 mmol, intermediate U) in MeCN (5 mL) were added DIEA (1.11 g, 8.61 mmol) and _T3P (3.29 g, 5.17 mmol, 50% solution in DMF). The resulting mixture was stirred at 60 ° C for 12 h. After completion, the reaction mixture was quenched with H ₂ O (5 mL) at 20 ° C and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with brine (10 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 0/1) to give the title compound (560 mg, 56% yield) as a yellow gum. LC-MS (ESI ⁺ ) m/z 581.3 (M+H) ⁺ .

Step 2-(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(5-(1-(2-(2-(benzyloxy)ethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (560 mg, 964 μmol) and Pd/C (56.0 mg, 52.8 μmol, 10 wt%) in THF (10 mL) was stirred at 20 °C under _H atmosphere (15 psi) for 1 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (393 mg, 83% yield) as a white solid. LC-MS(ESI ⁺ )m/z 491.3(M+H) ⁺ .

Step 3-2-(2-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)ethoxy)ethyl methanesulfonate. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-hydroxyethoxy)ethyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (150 mg, 305 μmol) and DIEA (59.2 mg, 458 μmol) in DCM (3 mL) was added MsCl (220 mg, 1.96 mmol, CAS #124-63-0) dropwise at 0 °C and the mixture was then stirred at 0 °C for 2 h. After completion, the reaction mixture was quenched with _H2O (5 mL) at 0°C and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (5 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give the title compound (180 mg, 72.47% yield) as a yellow gum. LC-MS (ESI ⁺ ) m/z 569.3 (M+H) ⁺ .

3-(3-methyl-2-oxo-4-(3-(piperidin-4-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazole oxazol-1-yl)piperidin-2,6-dione (Intermediate BS)

[0136] Step 1 - tert-Butyl 4-prop-2-ynylpiperidine-1-carboxylate. To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (500 mg, 2.20 mmol, CAS# 142374-19-4) _{, K2CO3} (912 mg, 6.60 mmol) in MeOH (15 mL) at 0°C was added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (507 mg, 2.64 mmol, CAS# 90965-06-3). The mixture was stirred at 25°C for 16 hours. After completion, the mixture was concentrated in vacuo. The mixture was diluted with _H2O (30 mL) and then extracted with EA (3 x 20 mL). The organic layer was washed with brine (2 x ₁₅ mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (490 mg, 99% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.25-4.03(m,2H),2.78-2.65(m,2H),2.22-2.13(m,2H),2.00(t,J＝2.8Hz,1H),1.85-1.72(m,2H),1.72-1.60(m,1H),1.48(s ,9H),1.30-1.15(m,2H).

Step ₂ - tert-Butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]prop-2-ynyl]piperidine-1-carboxylate. To a solution of tert-butyl 4-prop-2-ynylpiperidine-1-carboxylate (390 mg, 1.75 mmol), 3-(4-bromo-3-methyl-2-oxobenzimidazol-1-yl)piperidine-2,6-dione (393 mg, 1.16 mmol, Intermediate H) in DMSO (4 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (163 mg, 232 μmol), CuI (44.3 mg, 232 μmol) and DIPEA (752 mg, 5.82 mmol) under N 2. The mixture was stirred at 80° C. for 3 h. Upon completion, the mixture was filtered and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (450 mg, 80% yield) as a yellow solid. 2 _.66-2.59 (m,1H),2.56-2.52(m,1H),2.49-2.45(m,2H),2.11-1.97(m ^, 1H),1.82-1.71(m,3H),1.39(s,9H),1.25-1.10(m,2H),LC-MS(ESI ⁺ )m/z 503. 3(M+Na) ⁺ .

Step 3 - 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yl)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. A solution of tert-butyl 4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperidine-1-carboxylate (260 mg, 541 μmol) in TFA (6 mL) and DCM (6 mL) was stirred at 25 °C for 5 h. Upon completion, the reaction mixture was quenched with _H2O (5 mL) and extracted with EtOAc (8 mL x 2). The aqueous phase pH was adjusted to 3 to 4 with 1 N HCl, then extracted with EtOAc (8 mL x 4). The combined organic layers were washed with brine (3 mL x 3), dried _{over Na2SO4} and evaporated to give the title compound (220 mg) as a white solid. ¹ H NMR (400 MHz, DMSO- _d6 ) δ 7.69 (br dd, J = 7.6, 13.2 Hz, 1H), 7.58 (dt, J = 3.6, 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 7.09-7.05 (m, 1H), 7.03-6.96 (m, 1H), 5.39 (dd, J = 5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 3.12 (br d,J＝12.4Hz,2H),2.94-2.83(m,1H),2.77-2.59(m,5H),2.06-1.97(m,1H),1.85-1.72(m,3H),1.39-1.19(m,3H),1.11(s,1H).

3-[5-(7-Aminoheptyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (Intermediate BT)

Step 1 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hept-6-yn-1-yl]carbamate. To a stirred mixture of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (8.00 g, 23.7 mmol, Intermediate J), tert-butyl N-(hept-6-yn-1-yl)carbamate (10.00 g, 47.32 mmol, synthesized via steps 1-4 of Intermediate AN) and CuI (0.45 g, 2.37 mmol) in DMSO (40.00 mL)/TEA (20.00 mL) was added Pd( _PPh3 ) ₄ (2.73 g, 2.37 mmol) at rt under nitrogen atmosphere. The mixture was stirred at 85 ° C for 4h. After completion, the mixture was cooled to rt. The reactant was diluted with water (100mL) and extracted with EtOAc (3×100mL). The combined organic layer was washed with brine (2×100mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1: 2), and then further purified by reverse phase flash chromatography (column: WelFlash TM C18-I, 20-40?m, 330g; eluent A: water (plus 10mmol/L FA); eluent B: ACN; gradient: 40%-65% B, in 20min; flow rate: 80mL/min; detector: 220/254nm; collect the required elution with 60% B) and concentrated under reduced pressure to obtain the title compound (7.5g, 68% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.13(s,1H),7.25-7.23(m,1H),7.11-7.07(m,2H),6.82(t,J＝5.8Hz,1H),5.38(dd,J＝12.7,5.3Hz,1H),3.35(s,3H),2.95-2 .81(m,3H),2.79-2.56(m,2H),2.41(t,J＝7.0Hz,2H),2.05-1.99(m,1H),1.54(t,J＝7.0Hz,2H),1.41-1.37(m,13H). LC/MS(ESI,m/z):[(M+1)] ⁺ =469.3.

Step 2 - tert-Butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]heptyl]carbamate. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]hept-6-yn-1-yl]carbamate (8.00 g, 17.0 mmol) in MeOH (200.00 mL)/AcOH (10.00 mL) was added Pd/C (1.00 g, 9.40 mmol) at rt under nitrogen atmosphere. The reaction was purged with H ₂ three times and stirred under hydrogen atmosphere at rt for 16 h. After completion, the reaction mixture was filtered and the filter cake was washed with CH ₂ Cl ₂ (3×20 mL). The filtrate was concentrated under reduced pressure to give the title compound (7.5 g, 93% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 7.05-6.96 (m, 2H), 6.88-6.84 (m, 1H), 6.76 (t, J=5.8 Hz, 1H), 5.34 (dd, J=12.7, 5.3 Hz, 1H), 3.35 (s, 3H), 2.91-2.86 (m, 3H), 2.78-2.55 (m, 4H), 2.03-1.98 (m, 1H), 1.58 (t, J=7.4 Hz, 2H), 1.37 (s, 9H), 1.32-1.17 (m, 6H). LC/MS (ESI, m/z): [(M+1)] ⁺ =473.3.

Step 3 - 3-[5-(7-aminoheptyl)-3-methyl-2-oxo-1,3-benzodiazol-1-yl]piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]heptyl]carbamate (7.50 g, 15.9 mmol) in DCM (20.0 mL) was added HCl (4M) in 1,4-dioxane (20.0 mL) at rt under nitrogen atmosphere. The mixture was stirred at rt for 4 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was triturated with _Et2O to give the title compound (6.3 g, 97% yield) as an off-white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ11.09 (s, 1H), 7.92 (broad peak, 3H), 7.07-6.96 (m, 2H), 6.88-6.84 (m, 1H), 5.35 (dd, J = 12.8, 5.3Hz, 1H), 3.32 (s, 3H) 3.02-2.82 (m, 1 H),2.78-2.71(m,3H),2.68-2.56(m,3H),2.06-1.95(m,1H),1.62-1.51(m,4H),1.32-1.27(m,6H). LC/MS (ESI, m/z): [(M+1)] ⁺ =373.3.

1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylic acid (Intermediate BU)

Step 1 - 1-(4-Formylphenyl)-1H-pyrazole-4-carboxylic acid methyl ester. To a solution of (4-formylphenyl)boronic acid (10 g, 66.7 mmol, CAS#87199-17-5) and 1H-pyrazole-4-carboxylic acid methyl ester (12.6 g, 100 mmol, CAS#51105-90-9) in pyridine (100 mL) was added Cu(OAc) ₂ (24.2 g, 133 mmol). The mixture was stirred at 20 to 100 °C for 12 h. Upon completion, the mixture was poured into ice water (100 mL) and filtered, then the mixture was extracted with ethyl acetate (2 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL) and dried over sodium sulfate. Then filtered to give the filtrate and concentrated to give a residue. The product was purified by flash silica gel chromatography ( 80g Silica Flash Column, eluent 0 to 50% ethyl acetate/petroleum ether gradient, at 100 mL/min) to give the title compound as a yellow solid (1.5 g, 6.52 mmol, 10% yield). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝10.59 (br s, 1H), 10.04 (s, 1H), 9.79 (s, 1H), 8.20 (d, J＝8.4 Hz, 2H), 8.06 (d, J＝8.4 Hz, 2H), 3.82 (s, 3H).

Step 2-1-[4-(1,3-dioxolan-2-yl)phenyl]pyrazole-4-carboxylic acid methyl ester. To a solution of 1-(4-formylphenyl)-1H-pyrazole-4-carboxylic acid methyl ester (1 g, 4.34 mmol) in toluene (10 mL) was added ethylene glycol (808 mg, 13.0 mmol) and 4-methylbenzenesulfonic acid (74.8 mg, 434 μmol). The mixture was stirred at 20-130 ° C for 4 h. After completion, the mixture was poured into ice water (13 mL) and extracted with ethyl acetate (2×13 mL). The combined organic phases were washed with brine (2×13 mL) and then dried over sodium sulfate. It was then filtered to obtain a filtrate and concentrated to obtain a residue. By flash silica gel chromatography ( 12g The residue was purified by Silica Flash Column, eluent 0 to 18% ethyl acetate/petroleum ether gradient at 40 mL/min) to give the title compound (500 mg, 929 μmol, 21% yield) as a yellow oil. LC-MS (ESI+) m/z 231.0 (M+H) ⁺ .

[0266] Step 3 - 1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylic acid. To a solution of methyl 1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylate (400 mg, 1.46 mmol) in THF (3 mL), _H2O (1 mL) and MeOH (1 mL) was added _LiOH.H2O (244 mg, 5.83 mmol) in one portion. The mixture was stirred at 20°C for 10 h. Upon completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2 x 5 mL). The aqueous phase was acidified to pH = 4 with aqueous HCl (1 N) and extracted with ethyl acetate (2 x 5 mL). The combined organic phases were washed with brine (2 x 5 mL) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give the title compound (300 mg) as a white solid. LC-MS(ESI+)m/z 261.1(M+H) ⁺ .

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxylic acid (1R,3S)-3-(5-(1-(4-carboxylic acid)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BV) and (1R,3S)-3-(5-(1-(4-carboxylic acid)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BV) (4-(2-(2-(phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate BW)

Step 1 - (1R,3S)-3-(5-(1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxylic acid (300 mg, 1.15 mmol, intermediate BU) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (355 mg, 1.15 mmol, intermediate U) in ACN (3 mL) were added _T3P (2.20 g, 3.46 mmol, 50% solution in DMF) and DIEA (745 mg, 5.76 mmol) in one portion. The mixture was stirred at 20-60 ° C for 12 h. After completion, the mixture was poured into ice water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic phase was washed with brine (2×5 mL) and dried over sodium sulfate. The reaction was then filtered and the filtrate was concentrated to give a residue. The product was purified by flash silica gel chromatography ( 12g The residue was purified by Silica Flash Column, eluent 0 to 50% ethyl acetate/petroleum ether gradient at 50 mL/min) to give the title compound (420 mg, 541 μmol, 47% yield) as a yellow oil. LC-MS (ESI+) m/z 551.3 (M+H) ⁺ .

Step 2 - (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate and (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-(5-(1-(4-(1,3-dioxolan-2-yl)phenyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (400 mg, 726 μmol) was added a solution of HCl (2M, 2 mL) in THF (2.4 mL). The mixture was stirred at 60 ° C for 24 h. The reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 39%-69%, 10min) to give isopropylcarbamic acid (1R, 3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (100 mg, 197μmol, 27% yield) as a yellow oil. ( ¹ H NMR (400MHz, DMSO-d ₆ )δ=10.04(s,1H),9.79(s,1H),9.22(s,1H),8.37(s,1H),8.18-8.12(m,2H),8.11-8.06(m,2H),6.02(s,1H),5.75(s,1H),5.10-4.92(m,1H),3.62 -3.52(m,1H),3.05-2.96(m,1H), 2.00-1.82 (m, 3H), 1.75-1.66 (m, 3H), 1.53 (s, 9H), 1.02 (d, J = 6.4 Hz, 6H)) and (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 111 μmol, 15% yield) as a yellow oil ( ¹ H NMR (400MHz, DMSO-d ₆ )δ=12.31-12.06(m,1H),10.60(s,1H),10.04(s,1H),9.27(s,1H),8.41(s,1H),8.22-7.90(m,4H),7.06-6.85(m,1H),6.43(brs ,1H),5.01(br d,J＝4.4Hz,1H),3.58(qd,J＝6.8,13.6Hz,1H),3.14-2.99(m,1H),2.10-1.38(m,6H),1.03(d,J＝6.4Hz,6H)).

(Propan-2-yn-1-yl)carbamic acid tert-butyl methyl ester (Intermediate BX)

To a solution of tert-butyl N-methylcarbamate (10.0 g, 76.2 mmol, CAS#16066-84-5) in DMF (100 mL) was added NaH (3.66 g, 91.5 mmol) at 0°C. The reaction mixture was stirred at 25°C for 0.5 h. 3-bromoprop-1-yne (13.6 g, 114 mmol, CAS#106-96-7) was subsequently added. The mixture was stirred at 25°C for 2.5 hr. Upon completion, the reaction mixture was quenched by addition of _H2O (50 mL) and extracted with dichloromethane (3×500 mL). The combined organic layers were washed with brine (3×100 mL) and dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to give the title compound (4.80 g, 37% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d6) δ3.98 (d, J = 2.0Hz, 2H), 3.19 (s, 1H), 2.80 (s, 3H), 1.40 (s, 9H).

3-(3-methyl-4-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole- 1-yl)piperidin-2,6-dione (Intermediate BY)

Step 1-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)(methyl)carbamic acid tert-butyl ester. N-methyl-N-prop-2-ynyl-carbamic acid tert-butyl ester (2.00 g, 11.8 mmol, intermediate BX), 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (2.66 g, 7.88 mmol, intermediate H), CuI (150 mg, 787 μmol), Pd(PPh ₃ ) ₂ Cl ₂ (553 mg, 787 μmol), To a solution of molecular sieves (1.00 g, 7.88 mmol) and _Cs2CO3 (10.2 g, 31.5 mmol) in DMF (50 mL). The mixture was stirred at 80 °C under _N2 for 16 hr. Upon completion _, the mixture was filtered and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase flash (0.1% FA condition) to give the title compound (600 mg, 16% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ11.12(s,1H),7.23-6.90(m,3H),5.44-5.35(m,1H),4.29(s,2H),3.61(s,3H),3.54(s,1H),2.89(s,2H),2.95-2.80(m,1H), 2.77-2.59(m,2H),2.07-1.96(m,1H),1.42(s,9H).

Step 2 - 3-(3-methyl-4-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. To a solution of tert-butyl N-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]prop-2ynyl]-N-methyl-carbamate (100 mg, 234 μmol) in DCM (10 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 20 min. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (750 mg, 95% yield, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 349.2 (M+23) ⁺ .

1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (Intermediate BZ)

To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate H) in DMF (20 mL) was added TEA (448 mg, 4.44 mmol), Pd(dppf)Cl ₂ (162 mg, 221 μmol) and Et ₃ SiH (515 mg, 4.44 mmol). The reaction mixture was stirred at 80 °C under CO (50 Psi) atmosphere for 16 hours. Upon completion, the reaction mixture was concentrated in vacuo and purified by reverse phase (0.1% FA) to give the title compound (400 mg, 47% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 288.0 (M+H) ⁺ .

3-[4-(3,9-diazaspiro[5.5]undec-3-ylmethyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine -2,6-dione (Intermediate CA)

Step 1 - tert-Butyl 9-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate. To a solution of 1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (100 mg, 348 μmol, intermediate BZ) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (88.5 mg, 348 μmol, CAS# 173405-78-2) in THF (3 mL) and DMF (3 mL) was added tetraisopropoxytitanium (296 mg, 1.04 mmol, 308 μL). The mixture was stirred at 80 ° C for 2 hr, and then NaBH (OAc) ₃ (147 mg, 696 μ mol) was added to the mixture. The reaction mixture was stirred at 20 ° C for 16 hr. After completion, the residue was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA conditions) to give the title compound (145 mg, 79% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.10 (s, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.90-6.85 (m, 1H), 5.37 (dd, J = 5.2, 12.4 Hz, 1H), 3.66 (s, 3H), 3.65-3.60 (m, 2H), 3.30-3.23 (m, 4H ),2.94-2.84(m,1H),2.77-2.68(m,1H),2.65-2.57(m,1H),2.43-2.34(m,4H),2.05-1.96(m,1H),1.45-1.39(m,4H),1.38(s,9H),1.36-1.30(m,4 H); LC-MS (ESI ⁺ )m/z 526.2(M+H) ⁺ .

Step 2 - 3-[4-(3,9-diazaspiro[5.5]undecane-3-ylmethyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione. To a solution of tert-butyl 9-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (70.0 mg, 133 μmol) in DCM (1.5 mL) was added HCl/EtOAc (4 M, 1.50 mL). The reaction mixture was stirred at 20 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (60.0 mg, 97% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 426.3 (M+H) ⁺ .

Isopropylcarbamic acid (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (intermediate CB)

Step 1-(1-(tert-butyl)-3-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (10.0 g, 27.9 mmol, Intermediate AH) and 4-nitrophenyl chloroformate (8.46 g, 41.9 mmol, CAS#7693-46-1) in dichloromethane (100 mL) were added DMAP (342 mg, 2.80 mmol) and pyridine (6.64 g, 83.9 mmol). The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched with water (100 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (eluted with petroleum ether/ethyl acetate=3:1 to 1/1) to give the title compound (14 g, 26.7 mmol, 96% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.22-8.16 (m, 2H), 7.34-7.24 (m, 6H), 6.19-6.02 (m, 2H), 5.23-5.12 (m, 3H), 3.13-3.00 (m, 1H), 2.59-2.48 (m, 1H), 2.08-1.78 (m, 6H), 1.51 (s, 9H).

Step 2-Benzyl (1-(tert-butyl)-3-((1R,3S)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a mixture of benzyl (1-(tert-butyl)-3-((1R,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (14 g, 26.7 mmol) and propan- ₂ -amine (3.17 g, 53.5 mmol) in THF (140 mL) at 0 °C under N2 was added DIEA (17.3 g, 133 mmol) in one portion. The mixture was stirred at 20 °C for 10 h. Upon completion, the reaction mixture was quenched with water (100 mL) and then extracted with dichloromethane (3 x 140 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by silica gel chromatography (eluting with petroleum ether/ethyl acetate = 3:1 to 1/1) to give the title compound (10.8 g, 24.5 mmol, 92% yield) as a colorless gum. ¹ H NMR (400MHz, CDCl ₃ )δ=7.52-7.46(m,1H),7.38(br s,4H),6.32(br s,1H),6.13(br s,1H),5.30(s,1H),5.22-5.18(m,2H),5.09-5.07(m,1H),3.80(br d,J＝5.6Hz,1H),3.10(br d,J＝7.6Hz,1H),2.52-2.37(m,1H),2.04-1.98(m,1H),1.97-1.72(m,5H),1.58(s,8H),1.14(br d,J＝6.4Hz,6H).

Step 3-(1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of Pd/C (3.24 g, 3.06 mmol, 10 wt%) in ethanol (300 mL) was added benzyl (1-(tert-butyl)-3-((1R,3S)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (10.8 g, 24.4 mmol) under a stream of nitrogen. The suspension was degassed in vacuo and purged with hydrogen several times. The mixture was stirred under hydrogen (15 psi) at 20 °C for 10 h. Upon completion, the reaction was filtered to give a filtrate, which was filtered to give the title compound (5.1 g) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 5.2 (br s, 1H), 4.44 (br s, 1H), 3.8 (br d, J = 4.4Hz, 1H), 3.53 (br s, 2H), 3.11-2.94 (m, 1H), 2.55-2.41 (m, 1H), 2.05-1.72 (m, 6H), 1.62(s,9H),1.15(d,J＝6.4Hz,6H).

2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid (intermediate CC)

Step 1 - Methyl 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetate. To a solution of methyl 2-(2-hydroxyphenyl)acetate (993 mg, 5.98 mmol, CAS#22446-37-3), 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethanol (1.35 g, 7.17 mmol, CAS#208827-90-1) and _PPh3 (2.04 g, 7.77 mmol) in toluene (10 mL) was slowly added dropwise a solution of DIAD (1.57 g, 7.77 mmol, 1.51 mL) in toluene (10 mL) at 0°C. The reaction was then kept at 20°C under nitrogen atmosphere for 10 h. Upon completion, the reaction mixture was quenched with water (30 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 3/1 to 1/1) to give the title compound (625 mg, 1.86 mmol, 31% yield) as a colorless gum. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.27-7.22 (m, 1H), 7.19 (d, J = 7.2Hz, 1H), 6.93 (t, J = 7.2Hz, 1H), 6.88 (d, J = 8.4Hz, 1H), 4.21 (d, J = 2.4Hz, 2H), 4.14 (t, J = 5.2Hz, 2 H), 3.84 (t, J = 5.2Hz, 2H), 3.76-3.63 (m, 14H), 2.43 (t, J = 2.4Hz, 1H).

[0266] Step 2 - 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid. To a solution of methyl 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetate (625 mg, 1.86 mmol) in THF (6 mL) and _H2O (2 mL) was added _LiOH.H2O (311 mg, 7.43 mmol) in one portion. The mixture was stirred at 20 °C for 10 h. Upon completion, the reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3 x 20 mL) and the aqueous phase was acidified to pH = 4 with 1 N HCl. The mixture was then extracted with ethyl acetate (3 x 20 mL), the combined organic layers were washed with brine (3 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (220 mg) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.26-7.22(m,1H),7.21-7.18(m,1H),6.95-6.91(m,1H),6.84(d,J＝8.0Hz,1H),4.21(d,J＝2.4Hz,2H),4.19-4.17(m,2H),3.82 (td,J＝2.0,4.4Hz,2H),3.79-3.69(m,10H),3.61(s,2H),2.43(t,J＝2.4Hz,1H),1.29-1.24(m,1H).

Isopropylcarbamic acid (1S, 3R)-3-(1-(tert-butyl)-5-(2-(2-(2-(2-(2-prop-2-yn-1-yloxy) (4-(2-( ...

To a solution of (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (210 mg, 682 μmol, intermediate CB) in ACN (5 mL) was added 2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid (220 mg, 682 μmol, intermediate CC), DIEA (441 mg, 3.41 mmol) and _T3P (1.30 g, 2.05 mmol, 50% solution in DMF) in one portion. The mixture was then stirred at 60 °C under nitrogen atmosphere for 2 h. Upon completion, the reaction mixture was poured into saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. By flash silica gel chromatography ( 4g Silica Flash Column, eluent 0 to 50% ethyl acetate/petroleum ether gradient, 50 mL/min) to give the title compound as a yellow oil (95 mg, 154 μmol, 23% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ＝7.26-7.20 (m, 2H), 6.93 (t, J＝7.2 Hz, 1H), 6.86 (d, J＝8.0 Hz, 1H), 6.09 (s, 1H), 5.06 (br s, 1H), 4.67-4.49 (m, 1H), 4.13-4.10 (m, 4H), 3.82-3.79 (m, 2H), 3.69 (s, 2H), 3.58 (br dd,J＝3.6,5.6Hz,4H),3.53(dd,J＝4.0,5.6Hz,2H),3.47(dd,J＝3.6,5.6Hz,2H),3.38-3.31(m,2H),3.07-2.93(m,1H),2.35(t,J＝2.4Hz,2H),1.92-1.66( m, 6H), 1.23 (s, 9H), 1.07 (dd, J = 3.2, 6.4Hz, 6H).

3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)-1-methylpiperidin-2,6-dihydro- Ketone (CE intermediate)

To a solution of 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol, intermediate J) in DMF (16 mL) was added NaH (141 mg, 3.55 mmol, 60% dispersion in mineral oil) portionwise. The mixture was stirred at 0 °C under _N2 atmosphere for 30 min. MeI (503 mg, 3.55 mmol) was then added to the mixture, which was stirred at 25 °C for 12 h. The reaction mixture was quenched with _NH4Cl (saturated aqueous solution, 20 mL) at 25 °C and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over _{Na2SO4 ,} filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 0/1) to give the title compound (850 mg, 2.41 mmol, 82% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 354.2 (M+H) ⁺ .

3-(3-methyl-2-oxo-5-(3-(4-(piperazin-1-yl)butoxy)propyl)-2,3-dihydro-1H-benzo[d] Imidazol-1-yl)piperidine-2,6-dione (Intermediate CF)

Step 1 - tert-Butyl 4-(4-hydroxybutyl)piperazine-1-carboxylate. To a stirred solution of tert-butyl piperazine-1-carboxylate (39.00 g, 209.4 mmol) and 4-bromobutan-1-ol (48.06 g, 314.1 mmol) in ACN (1000 mL) was added portionwise K ₂ CO ₃ (115.76 g, 837.6 mmol) and KI (17.38 g, 104.7 mmol) at rt under nitrogen atmosphere. The resulting mixture was stirred at 90 °C under nitrogen atmosphere overnight. After completion, the mixture was cooled to room temperature and filtered. The filter cake was washed with MeCN (3×50 mL), and the filtrate was concentrated under reduced pressure. The residue was quenched with water and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (30:1) to give the title compound (19.7 g, 36% yield) as a pale yellow oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 5.62-5.57 (m, 1H), 3.57 (t, J=4.9 Hz, 2H), 3.49-3.41 (m, 4H), 2.46-2.42 (m, 4H), 2.42-2.37 (m, 2H), 1.69-1.63 (m, 4H), 1.45 (s, 9H). LC/MS (ESI, m/z): [(M+1)] ⁺ =259.3.

Step 2 - tert-Butyl 4-[4-(prop-2-yn-1-yloxy)butyl]piperazine-1-carboxylate. To a stirred solution of tert-butyl 4-(4-hydroxybutyl)piperazine-1-carboxylate (31.50 g, 121.9 mmol) in DMF (300.00 mL) was added NaH (5.85 g, 244 mmol, 60% dispersion in mineral oil) portionwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0°C under nitrogen atmosphere. To the above mixture was added a solution of propargyl bromide (29.01 g, 243.9 mmol) in DMF (50.00 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at rt under nitrogen atmosphere. Upon completion, the reaction was quenched with sat. NH ₄ Cl (aq.) at 0°C and extracted with EtOAc (3×400 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO _4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE/EtOAc=5/1 to give the title compound (19.7 g, 55% yield) as a brown oil. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.14 (d, J=2.4 Hz, 2H), 3.54 (t, J=6.1 Hz, 2H), 3.48-3.41 (m, 4H), 2.43 (t, J=2.4 Hz, 1H), 2.42-2.34 (m, 6H), 1.71-1.53 (m, 4H), 1.47 (s, 9H). LC/MS (ESI, m/z): [(M+1)] ⁺ ＝297.3.

Step 3 - tert-Butyl 4-[4-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)butyl]piperazine-1-carboxylate. To a stirred solution of 3-(5-bromo-3-methyl-2-oxo-1,3-benzodiazol-1-yl)piperidine-2,6-dione (10.00 g, 29.572 mmol, Intermediate J) and tert-butyl 4-[4-(prop-2-yn-1-yloxy)butyl]piperazine-1-carboxylate (13.15 g, 44.36 mmol) in DMSO (200.00 mL) and TEA (49.20 mL) was added portionwise Pd(PPh ₃ ) ₄ (3.42 g, 2.96 mmol) and CuI (0.56 g, 2.9 mmol). The resulting mixture was purged with nitrogen 3 times. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. After completion, the mixture was cooled to rt and diluted with water (100 mL). The resulting mixture was washed with EA (3×150 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na ₂ SO _4. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ /MeOH (20: 1) to give the title compound (8.3 g, 51% yield) as a yellow oil. ¹ HNMR (400MHz, chloroform-d) δ8.81(s,1H),7.20(dd,J＝8.1,1.5Hz,1H),7.12(d,J＝1.4Hz,1H),6.76(d,J＝8.1Hz,1H),5.21(dd,J＝12.7,5.3Hz,1H),4.36(s,2H),3 .60(t,J＝6.1Hz,2H),3.46-3.42(m,7H),3.01-2.88(m,1H),2.88-2.66(m,2H),2.42-2.36(m,6H),2.28-2.17(m,1H),1.70-1.59(m,4H),1.47(s,9H) . LC/MS (ESI, m/z): [(M+1)] ⁺ =554.4.

Step 4 - tert-Butyl 4-(4-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]butyl)piperazine-1-carboxylate. To a stirred solution of tert-butyl 4-[4-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]prop-2-yn-1-yl]oxy)butyl]piperazine-1-carboxylate (8.00 g, 14.4 mmol) in _CH3OH (100.00 mL) and THF (10.00 mL) was added Pd/C (4.00 g, 37.6 mmol) at rt. The resulting mixture was purged with hydrogen three times and stirred under hydrogen atmosphere at rt overnight. After completion, the resulting mixture was filtered and the filter cake was washed with THF (3 x 30 mL). The solution was concentrated under reduced pressure to give the title compound (7.5 g) as a pale yellow oil. LC/MS (ESI, m/z): [(M+1)] ⁺ =558.4.

Step 5 - 3-(3-methyl-2-oxo-5-[3-[4-(piperazin-1-yl)butoxy]propyl]-1,3-benzodiazol-1-yl)piperidine-2,6-dione dihydrochloride. To a stirred solution of tert-butyl 4-(4-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-1,3-benzodiazol-5-yl]propoxy]butyl)piperazine-1-carboxylate (7.50 g, 13.5 mmol) in DCM (100.00 mL) was added 4M HCl(g) in 1,4-dioxane (30.00 mL) at rt under nitrogen atmosphere. The resulting mixture was stirred at rt under nitrogen atmosphere for 1 h. Upon completion, _Et2O (200 mL) was added to the mixture. The precipitated solid was collected by filtration and washed with _Et2O (3 x 100 mL) to give the title compound (5 g, 70% yield) as a pale yellow ^solid.1H NMR (400 MHz, DMSO- _d6 ) δ 11.56 (broad peak, 1H), 11.08 (s, 1H), 9.52 (broad peak, 2H), 7.05 (d, J = 1.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.88 (dd, J = 8.1, 1.6 Hz, 1H), 5.35 (dd, J = 12.7, 5.4 Hz, 1H), 3.68-3.64 (d, J = 1. (m,2H),3.51-3.36(m,9H),3.27-3.11(m,4H),2.99-2.86(m,1H),2.78-2.58(m,4H),2.56-2.53(m,2H),2.03-1.97(m,1H),1.93-1.66(m,4H),1.5 8-1.53(m,2H). LC/MS (ESI, m/z): [(M+1)] ⁺ =458.3.

3-(4-(3-(3-(3-aminopropoxy)propoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]Imidazol-1-yl)piperidine-2,6-dione (Intermediate CG)

Step 1 - tert-Butyl N-[3-(methylsulfonyloxy)propyl]carbamate. To a stirred solution of tert-butyl N-(3-hydroxypropyl)carbamate (92.6 g, 528 mmol) and TEA (109.8 mL, 792.7 mmol) in DCM (800 mL) was added dropwise a solution of Ms-Cl (60.5 g, 528 mmol) in DCM (200 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at rt under nitrogen atmosphere for 30 min. Upon completion, the reaction mixture was diluted with water (2 L) and extracted with _CH2Cl2 (3 x 800 mL). The combined organic layers were washed with brine (1.5 L) and dried _over anhydrous _Na2SO4 . After filtration _, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (3:2) to give the title compound (112 g, 84% yield) as a light brown solid. ¹ H NMR (400 MHz, CHLOROFORM-d) δ 4.93-4.90 (m, 1H), 4.26-4.22 (m, 2H), 3.24-3.19 (m, 2H), 3.01 (s, 3H), 1.94-1.88 (m, 2H), 1.38 (s, 9H). LC/MS (ESI, m/z): [(M+1)] ⁺ =254.2.

Step 2 - tert-Butyl N-[3-(3-hydroxypropoxy)propyl]carbamate. To a solution of propane-1,3-diol (50 g, 657 mmol) in DMF (500 mL) was added sodium hydride (4.8 g, 200 mmol, 60% dispersion in mineral oil) at 0°C. The mixture was stirred for 15 min. To the above mixture was added a solution of tert-butyl N-[3-(methylsulfonyloxy)propyl]carbamate (25.3 g, 100 mmol) in DMF (150 mL) at rt. The mixture was stirred at rt for 16 h. Upon completion, the reaction was quenched with sat. NH ₄ Cl (aq.) (200 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The mixture was diluted with brine (1.5 L) and extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/EtOAc (2:1) to give the title compound (13.7 g, 59% yield) as a light yellow oil. ¹ H NMR (400 MHz, chloroform-d) δ 5.05-5.02 (m, 1H), 3.69-3.64 (m, 2H), 3.52-3.49 (m, 2H), 3.43-3.40 (m, 2H), 3.15-3.109 (m, 3H), 1.77-1.72 (m, 2H), 1.69-1.64 (m, 2H), 1.37 (s, 9H). LC/MS (ESI, m/z): [(M+1)] ⁺ = 234.2.

Step 3 - tert-Butyl N-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate. To a solution of tert-butyl N-[3-(3-hydroxypropoxy)propyl]carbamate (12.5 g, 53.6 mmol) in THF (300 mL) was added sodium hydride (2.6 g, 110 mmol, 60% dispersion in mineral oil) at 0°C. The mixture was stirred for 15 min. Subsequently, a solution of 3-bromoprop-1-yne (6.4 g, 54 mmol) in THF (50 mL) was added and the mixture was allowed to warm to rt and stirred for 16 h. Upon completion, the reaction was quenched with sat. NH ₄ Cl (aq.) (200 mL) at 0°C. The resulting mixture was diluted with brine (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to give the title compound (9.2 g, 60% yield) as a light yellow solid. ¹ H NMR (400 MHz, chloroform-d) δ 4.93 (broad peak, 1H), 4.11 (d, J = 2.4 Hz, 2H), 3.57 (t, J = 6.3 Hz, 2H), 3.46 (q, J = 6.2 Hz, 4H), 3.19 (d, J = 7.6 Hz, 2H), 2.42 (t, J = 2.4 Hz, 1H), 1.83 (p, J = 6.3 Hz, 2H), 1.71 (p, J = 6.2 Hz, 2H), 1.41 (s, 9H). LC/MS (ESI, m/z): [(M+1)] ⁺ = 272.3.

Step 4 - tert-Butyl N-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate. To a stirred solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione (2 g, 5.9 mmol, intermediate H), tert-butyl N-[3-[3-(prop-2-yn-1-yloxy)propoxy]propyl]carbamate (3 g, 11 mmol) and TEA (15 mL) in DMA (30 mL) were added CuI (112.64 mg, 0.591 mmol) and Pd(PPh) at rt under nitrogen atmosphere. ₃ ) ₄ (683.44 mg, 0.591 mmol). The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 6 h. After completion, the mixture was cooled to rt and then concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (column, C18 silica gel; mobile phase, ACN/aq.FA (10 mmol/L), 35% to 60% gradient, within 15 min; detector, UV 254 nm) to give the title compound (1.4 g, 45% yield) as a light brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.12(s,1H),7.18(dd,J＝7.9,1.2Hz,1H),7.13(dd,J＝7.9,1.2Hz,1H),7.03(t,J＝7.9Hz,1H),6.76-6.72(m,1H),5.41(dd,J＝12.7,5.4Hz,1H),4.43(s, 2H),3.64(s,3H),3 .62-3.55(m,2H),3.42(t,J＝6.4Hz,2H),3.35(d,J＝12.6Hz,2H),3.01-2.82(m,3H),2.77-2.56(m,2H),2.06-1.99(m,1H),1.82-1.74(m,2H),1.62- 1.55(m,2H),1.37(s,9H). LC/MS(ESI,m/z):[(M+1)] ⁺ =529.3.

Step 5 - tert-Butyl N-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate. To a stirred solution of tert-butyl N-[3-[3-([3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]prop-2-yn-1-yl]oxy)propoxy]propyl]carbamate (600 mg, 1 mmol) in THF (15 mL) was added Pd/C (300 mg, 0.3 mmol, 10 wt%) at rt under nitrogen atmosphere. The resulting mixture was purged with H ₂ three times and stirred at rt under hydrogen atmosphere for 4 h. After completion, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the title compound (580 mg, 96% yield) as a light brown solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 7.00-6.94 (m, 2H), 6.88-6.84 (m, 1H), 6.79-6.76 (m, 1H), 5.37 (dd, J = 12.5, 5.4Hz, 1H), 3.57 (s, 3H), 3.48-3.39 ( m,6H),3.37-3.34(m,2H),3.01-2.84(m,5H),2.79-2.57(m,2H),2.06-1.9 5(m,1H),1.86-1.80(m,2H),1.79-1.69(m,2H),1.64-1.57(m,2H),1.37(s ,9H). LC/MS(ESI,m/z):[(M+1)] ⁺ =533.3.

Step 6 - 3-(4-[3-[3-(3-aminopropoxy)propoxy]propyl]-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-1-yl)piperidine-2,6-dione hydrochloride. To a stirred solution of tert-butyl N-[3-(3-[3-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-1,3-benzodiazol-4-yl]propoxy]propoxy)propyl]carbamate (580 mg, 1.1 mmol) in 1,4-dioxane (7 mL) was added dropwise HCl (4 M in dioxane) (7 mL) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at rt under nitrogen atmosphere for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (10 mL) and concentrated under reduced pressure to give the title compound (489 mg, 96% crude yield) as a light green solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.11 (s, 1H), 7.81 (broad peak, 3H), 7.05-6.95 (m, 2H), 6.89-6.85 (m, 1H), 5.38 (dd, J=12.5, 5.4 Hz, 1H), 3.58 (s, 3H), 3.45-3.41 (m, 8H), 3.01-2.78 (m, 5H), 2.78-2.58 (m, 2H), 2.06-1.95 (m, 1H), 1.90-1.69 (m, 6H). LC/MS(ESI,m/z):[(M+1)] ⁺ =433.3.

4-[(7'-cyclopentyl-6'-oxo-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino]- 3-Methyl-benzenesulfonyl chloride (intermediate CH)

Step 1-1-(4-chloro-2-(methylthio)pyrimidin-5-yl)cyclopropanecarboxylic acid ethyl ester. To a solution of NaH (2.43 g, 60.8 mmol, 60% dispersion in mineral oil) in DMF (60 mL) at 0°C, and then slowly added a solution of ethyl 2-(4-chloro-2-methylthio-pyrimidin-5-yl)acetate (6 g, 24.3 mmol, CAS#61727-34-2) and 1,2-dibromoethane (6.85 g, 36.5 mmol, CAS#106-93-4) in DMF (60 mL) at 0°C. The solution was then stirred at 25°C for 0.5 h. Upon completion, the mixture was slowly poured into sat. NH ₄ Cl (60 mL) at 0°C, and the solution was extracted with EtOAc (50 ml×3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 15/1 to 10/1) to give the title compound (4.5 g, 63% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 272.9 (M+H) ⁺ .

Step 2-1-(4-(Cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)cyclopropanecarboxylic acid ethyl ester. To a solution of 1-(4-chloro-2-methylthio-pyrimidin-5-yl)cyclopropanecarboxylic acid ethyl ester (4.8 g, 17.6 mmol) in dioxane (10 mL) were added TEA (2.67 g, 26.4 mmol) and cyclopentylamine (3.75 g, 44.0 mmol). The mixture was then stirred at 60° C. for 12 h. Upon completion, the mixture was diluted with water (20 ml) and extracted with CH ₂ Cl ₂ (20 ml×3). The organic layer was washed with brine (20 ml×3), and the combined organic layers were then concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=8/1 to 4/1) to give the title compound (5 g, 85% yield) as a red oil. LC-MS(ESI ⁺ )m/z 322.0(M+H) ⁺ .

Step 3 - 7'-cyclopentyl-2'-(methylthio)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. To a solution of 1-[4-(cyclopentylamino)-2-methylthio-pyrimidin-5-yl]cyclopropanecarboxylic acid ethyl ester (4.8 g, 14.9 mmol) in THF (80 mL) was added NaH (1.19 g, 29.9 mmol, 60% dispersion in mineral oil). The mixture was then stirred at 0-60° C. for 1 h. Upon completion, the mixture was quenched with HCl (1 M, 20 ml) at 0° C., and the solution was then extracted with EtOAc (20 ml×3). The combined organic layers were washed with brine (20 ml×3), and the organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 10/1) to give the title compound (3.2 g, 73% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 276.0 (M+H) ⁺ .

Step 4 - 7'-cyclopentyl-2'-(methylsulfonyl)spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. To a solution of 7'-cyclopentyl-2'-methylsulfanyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (1 g, 3.63 mmol) in THF (15 mL) and H ₂ O (15 mL) was added potassium persulfate (5.58 g, 9.08 mmol). The mixture was then stirred at 30° C. for 4 h. After completion, the reaction mixture was filtered to give a solution. The solution was then diluted with water (20 ml) and extracted with EtOAc (20 ml×3). The combined organic layers were washed with brine (20 ml×3) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 2/1) to give the title compound (1.1 g, 98% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 308.0 (M+H) ⁺ .

Step 5 - 2'-((4-(Benzylthio)-2-methylphenyl)amino)-7'-cyclopentylspiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one. To a solution of 7'-cyclopentyl-2'-methanesulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (0.3 g, 976 μmol) in toluene (10 mL) were added Pd(OAc) ₂ (21.9 mg, 97.6 _μmol ) and BINAP (91.2 mg, 146 μmol), _Cs2CO3 (954 mg, 2.93 mmol), Molecular sieves (300 mg, 976 μmol) and 4-benzylsulfanyl-2-methyl-aniline (224 mg, 976 μmol, intermediate M). The mixture was stirred at 100 ° C under N ₂ atmosphere for 12 h. After completion, the reaction mixture was poured into water (30 ml) and extracted with EtOAc (10 ml×3). The organic layer was dried over Na ₂ SO ₄ , and the solution was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=8/1 to 3/1) and pre-HPLC (FA conditions) to give the title compound (74 mg, 13% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 457.0 (M+H) ⁺ .

Step 6-4-((7'-cyclopentyl-6'-oxo-6',7'-dihydrospiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino)-3-methylbenzene-1-sulfonyl chloride. To a solution of 2'-(4-benzylsulfanyl-2-methyl-phenylamino)-7'-cyclopentyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (50 mg, 110 μmol) in AcOH (1 mL) and HCl (0.3 mL) was added NCS (58.5 mg, 438 μmol) at 0°C. The mixture was then stirred at 0-25°C for 10 min. Upon completion, the mixture was diluted with water (5 ml) and extracted with EtOAc (5 ml×3). _The organic layer was dried over _Na2SO4 and concentrated under reduced pressure to give the residue as a yellow solid (40 mg). LC-MS (ESI ⁺ ) m/z 433.1 (M+H) ⁺ .

1-(3,6,9,12-Tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid (Intermediate CI)

Step 1 - Methyl 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylate and methyl 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-3-carboxylate. To a solution of 3,6,9,12-tetraoxapentadeca-14-yn-1-yl 4-methylbenzenesulfonate (4.2 g, 10.87 mmol, synthesized via Step 1 of Intermediate BK) and methyl 1H-pyrazole-5-carboxylate (1.37 g, 10.9 mmol) in DMF ₍ 60 mL) were added KI (180 mg, 1.09 mmol) and _Cs2CO3 (7.08 g, 21.7 mmol) in one portion. The resulting mixture was stirred at 70°C for 2 h. After completion, the reaction mixture was quenched with H ₂ O (60 mL) at 20 ° C and extracted with EtOAc (60 mL × 3). The combined organic layer was washed with brine (60 mL × 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give 1-(3,6,9,12-tetraoxapentadeca-14-alkyne-1-yl)-1H-pyrazole-5-carboxylic acid methyl ester (1.2 g, 32% yield, ¹ H NMR (400 MHz, DMSO-d ₆ )δ＝7.58(d, J＝2.0 Hz, 1H), 6.87(d, J＝2.0 Hz, 1H), 4.66(t, J＝5.6 Hz, 2H), 4.13(d, J＝2.4 Hz, 2H), 3.83(s, 3H), 3.74(t, J＝5.6 Hz, 2H), 3.55-3.50(m, 4H), 3.47-3.41(m, 9H)) and 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-3-carboxylic acid methyl ester (1.5 g, 41% yield, ¹ H NMR (400 MHz, DMSO-d ₆ )δ=7.02(d,J=2.4Hz,1H),5.90(d,J=2.4Hz,1H),3.51(t,J=5.2Hz,2H),2.99-2.93(m,5H),2.73-2.61(m,13H),2.50(s,2H)).

Step 2-1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid. A solution of methyl 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylate (1.2 g, 3.53 mmol) and LiOH.H ₂ O (591 mg, 14.1 mmol) in THF (10 mL) and H ₂ O (5 mL) was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 20° C. and extracted with EtOAc (20 mL×3). The aqueous phase was then adjusted to pH=3 to 4 and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give the title compound (700 mg) as a yellow gum. LC-MS (ESI ⁺ ) m/z 327.2 (M+H) ⁺ .

Isopropylcarbamic acid (1R,3S)-3-(5-(1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyridine (tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate CJ)

A solution of 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.23 mmol, intermediate CI), (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (455 mg, 1.48 mmol, intermediate U), DIEA (318 mg, 2.46 mmol), T ₃ P (2.35 g, 3.69 mmol, 50% solution in DMF) in MeCN (10 mL) was stirred at 80° C. for 12 h. After completion, the mixture was quenched with NH ₄ Cl (saturated aqueous solution, 10 mL) and extracted with EtOAc (20 ml×2). The combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , PE:EtOAc=0:1) to give the title compound (490 mg, 64% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 617.4 (M+H) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.10 (br s, 1H), 7.55 (s, 1H), 6.66 (br s, 1H), 6.21 (s, 1H), 5.15 (br s,1H),4.77(t,J＝5.2Hz,2H),4.66-4.52(m,1H),4.17(d,J＝2.4Hz,2H),3.88(t,J＝5.2Hz,2H),3.85-3.76(m,1H),3.68-3.62(m,4H),3.59-3.54(m,4 H),3.52-3.47(m,4H),3.17-3.07(m,1H),2.52-2.45(m,1H),2.43(t,J＝2.4Hz,1H),2.10-2.01(m,1H),1.98-1.92(m,1H),1.89-1.84(m,2H),1.65 (s,9H),1.62(br d,J＝6.4Hz,2H),1.17-1.13(m,6H).

(1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate (intermediate CK)

Step 1-(1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate. To a solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (500 mg, 956 μmol, synthesized via Step 1 of Intermediate U) and pyrrolidine (136 mg, 1.91 mmol) in THF (5 mL) was added DIEA (618 mg, 4.78 mmol). The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched with _H2O (8 mL) at 25 °C and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL x 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 3/1 to 2/1) to give the title compound (360 mg, 791 μmol, 83% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 455.2 (M+H) ⁺ .

Step 2-(1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate. To a solution of (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate (360 mg, 791 μmol) in THF (4 mL) was added Pd/C (30 mg, 28.3 μmol, 10 wt%) in one portion. The mixture was stirred at 25 °C under _H atmosphere (15 psi) for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (250 mg, 780 μmol, 99% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 321.5 (M+H) ⁺ .

(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy) (ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate (Intermediate CL)

To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate (250 mg, 780 μmol, intermediate CK) and 2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]pyrazole-3-carboxylic acid (210 mg, 743 μmol, intermediate BE) in ACN (2 mL) was added T ₃ P (1.42 g, 2.23 mmol, 50% solution in DMF) and DIEA (480 mg, 3.72 mmol) in one portion. The mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched with H ₂ O (3 mL) at 25 °C and extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 4g The residue was purified by Silica Flash Column, eluent 0 to 100% ethyl acetate/petroleum ether gradient at 50 mL/min) to give the title compound as an orange solid. LC-MS (ESI ⁺ ) m/z 385.5 (M+H) ⁺ .

3-(Methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrrolidone Oxazole-5-carboxylic acid (Intermediate CM)

Step 1 - Ethyl 3-(methoxymethyl)-1H-pyrazole-5-carboxylate. To a solution of 3-methoxyprop-1-yne (10.2 g, 145 mmol, CAS# 627-41-8) in toluene (80 mL) was added ethyl 2-diazoacetate (18.2 g, 160 mmol). The mixture was stirred at 110 °C for 6 h. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 5/1 to 1/1) to give the title compound (10 g, 37% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.71 (s, 1H), 6.81 (s, 1H), 4.67 (s, 1H), 4.55 (s, 2H), 4.40 (q, J = 7.2Hz, 3H), 3.44 (s, 1H), 3.41 (s, 3H), 1.43 (s, 1H), 1.42-1.38 ( m,3H).

Step 2 - 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid ethyl ester and 5-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-3-carboxylic acid ethyl ester. 3-(methoxymethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (2.50 g, 13.6 mmol), 4-methylbenzenesulfonic acid 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl ester (3.87 g, 11.3 mmol, synthesized via step 1 of intermediate BE), Cs ₂ CO ₃ A solution of 5-(methoxymethyl)-1-(2-( _{2-(2-(prop-2 -} yn- ₁ -yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole- ₃ -carboxylic acid ethyl ester (1.50 g, 34% yield) was obtained as a colorless oil ( ¹ H NMR (400 MHz, CD ₃₄ )). Cl)δ6.74(s,1H),6.54(s,2H),6.43-6.39(m,5H),4.20(d,J＝2.4Hz,2H),3.87(t,J＝6.0Hz,3H),3.67-3.53(m,8H),3.34(s,3H),2.44(t,J＝2.0Hz,1H),1 .39(t,J＝7.2Hz,4H); LC-MS(ESI ⁺ )m/z 355.2(M+H) ⁺ )

and ethyl 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (0.68 g, 15% yield) ( ¹ H NMR (400 MHz, CD ₃ Cl) δ 6.84 (s, 1H), 4.75 (t, J=6.0 Hz, 2H), 4.46 (s, 2H), 4.34 (q, J=7.2 Hz, 2H), 4.20 (d, J=2.4 Hz, 2H), 3.86 (t, J=6.0 Hz, 3H), 3.73-3.55 (m, 12H), 3.40 (s, 3H), 2.43 (t, J=2.0 Hz, 1H), 1.37 (t, J=7.2 Hz, 4H); LC-MS (ESI ⁺ ) m/z 355.2(M+H) ⁺ ).

Step 3 - 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid. A solution of ethyl 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylate (1.50 g, 4.23 mmol), LiOH.H ₂ O (888 mg, 21.2 mmol) in THF (10 mL) and H ₂ O (5 mL) was stirred at 40° C. for 4 h. After completion, the mixture was quenched with NH ₄ Cl (saturated aqueous solution, 20 mL), and then extracted with EtOAc (20 mL×2). The aqueous layer was acidified to pH<4 with HCl/1M (10 mL), and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (80 mL x 3), dried over _Na2SO4 , and concentrated in _vacuo.1H ^NMR (400 MHz, _CD3Cl ) δ = 6.90 (s, 1H), 4.77 (t, J = 5.6 Hz, 2H), 4.48 (s, 2H), 4.21 (d, J = 2.4 Hz, 3H), 3.85 (t, J = 5.6 Hz, 3H), 3.72-3.58 (m, 11H), 3.40 (s, 3H); LC-MS (ESI ⁺ ) m/z 327.2 (M+H) ⁺ .

Isopropylcarbamic acid (1R,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-(2-(2-(2-propan- (2-Alkyn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Medium Intermediate CN)

A solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (472 mg, 1.53 mmol, intermediate U), 3-(methoxymethyl)-1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (500 mg, 1.53 mmol, intermediate CM), T ₃ P (2.92 g, 4.60 mmol, 50% solution in DMF), DIEA (990 mg, 7.66 mmol) in ACN (10 mL) was stirred at 60° C. for 12 h. After completion, the mixture was quenched with H ₂ O (10 mL) and then extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (20 ml×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , EtOAc:PE=2:1) to give the title compound (600 mg, 57% yield) as a yellow oil. ¹ H NMR (400MHz, CD ₃ Cl) δ8.26-8.19(m,1H),6.65(s,1H),6.32(s,1H),5.19-5.15(m,1H),4.74-4.71(m,2H),4.50(s,2H),4.15(d,J＝1.6Hz,2H),4.14(br s,1H),3.84(br t,J＝4.8Hz,2H),3.59(br d,J＝4.8Hz,2H),3.58-3.53(m,3H),3.49(br d,J＝4.4Hz,4H),3.44(br s,1H),3.44(s,3H),2.44(br d,J＝2.0Hz,1H),2.05(s,2H),1.73(s,9H),1.27(s,3H),1.15(br d,J＝6.4Hz,6H). LC-MS(ESI ⁺ )m/z 617.4(M+H) ⁺ .

4-((6-bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methyl Benzene-1-sulfonyl chloride (intermediate CO)

Step 1 - 4-(Cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester. To a solution of 4-chloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (10 g, 42.9 mmol, CAS#1074-68-6) in dioxane (100 mL) was added TEA (8.70 g, 85.9 mmol) and cyclopentylamine (4.39 g, 51.5 mmol, CAS#1003-03-08). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (100 mL) at 25 °C and extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (11.5 g, 40.8 mmol, 95% yield) as an orange oil. LC-MS(ESI ⁺ )m/z 272.2(M+H) ⁺ .

Step 2-(4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol. To a solution of ethyl 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylate (11.5 g, 40.8 mmol) in DCM (130 mL) was added DIBAL-H (1 M, 61.31 mL) dropwise at -65 °C and stirred at -50-55 °C under _N2 atmosphere for 3 h. Upon completion, the reaction mixture was quenched with MeOH (120 mL) at -65 °C and then diluted with DCM (120 mL) and extracted with DCM (120 mL x 3). The combined organic layers were washed with brine (120 mL x 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 40g The residue was purified by Silica Flash Column, eluent 0 to 100% ethyl acetate/petroleum ether gradient at 100 mL/min) to give the title compound (5.5 g, 22.9 mmol, 56% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 240 (M+H) ⁺ .

Step 3 - 4-(Cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde. To a solution of (4-(cyclopentylamino)-2-(methylthio)pyrimidin-5-yl)methanol (2 g, 4.18 mmol) in EtOAc (50 mL) was added MnO ₂ (14.5 g, 83.5 mmol). The mixture was stirred at 50 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title product as an orange oil (1.5 g). LC-MS (ESI ⁺ ) m/z 238.1 (M+H) ⁺ .

Step 4 - 8-Cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. A solution of 4-(cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehyde (3.8 g, 16.0 mmol) and ethyl acetate (4.23 g, 48.0 mmol) in THF (45 mL) was purged with nitrogen and cooled to -5°C internal temperature in a MeOH-ice bath. LiHMDS (1 M, 48.04 mL) was then added, slowly enough to maintain the internal temperature at -5°C. The mixture was then stirred at 0-20°C under a _N2 atmosphere for 12 h. The resulting red solution was cooled to -3°C internal temperature in an ice-water bath, then EtOH (45 mL) was added by cannula, slowly enough to maintain the internal temperature at -3°C. The mixture was stirred in the ice bath for 1 h, then the cooling bath was removed, then the solution was allowed to warm to 20°C internal temperature, and stirring was continued for 1 h. The solvent was evaporated, the residue was diluted with water (45 mL) and brine (50 mL×3), and the aqueous layer was extracted with EtOAc (20 mL, then 45 mL×2). The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (3 g, 11.4 mmol, 72% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 262.2 (M+H) ⁺ .

Step 5-6-bromo-8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (3 g, 11.4 mmol) in DMF (30 mL) was added NBS (2.25 g, 12.6 mmol). The mixture was then stirred at 20 °C for 12 h. The reaction mixture was quenched with water (30 mL) at 25 °C and then extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 3/1) to give the title compound (1 g, 2.94 mmol, 26% yield) as an orange solid. LC-MS(ESI ⁺ )m/z 342.1(M+H) ⁺ .

Step 6 - 6-Bromo-8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-bromo-8-cyclopentyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (1 g, 2.94 mmol) in THF (20 mL) and H ₂ O (20 mL) was added potassium hydrogen persulfate (4.52 g, 7.35 mmol) in one portion. The mixture was stirred at 30° C. for 3 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (900 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 373.9 (M+H) ⁺ .

Step 7 - 2-((4-(Benzylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one. To a solution of 6-bromo-8-cyclopentyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (900 mg, 2.42 mmol) and 4-benzylthio-2-methyl-aniline (554 mg, 2.42 mmol, intermediate M) in IPA (10 mL) was added TFA (5.51 g, 48.36 mmol). The mixture was stirred at 120 °C for 24 h. Upon completion, the reaction mixture was quenched with water (10 mL) at 25 °C and then extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. By flash silica gel chromatography ( 14g The residue was purified by Silica Flash Column, eluent 0 to 100% ethyl acetate/petroleum ether gradient at 100 mL/min) to give the title compound (300 mg, 575 μmol, 24% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 523 (M+H) ⁺ .

Step 8 - 4-((6-bromo-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride. To a solution of 2-((4-(phenylmethylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentylpyrido[2,3-d]pyrimidin-7(8H)-one (300 mg, 575 μmol) in HCl (1.5 mL) and AcOH (5 mL) was added NCS (307 mg, 2.30 mmol) at 0°C. The mixture was stirred at 0-25°C for 2 h. Upon completion, the reaction mixture was quenched with water (10 mL) at 25°C and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL x 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give the title compound (280 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 373.9 (M+H) ⁺ .

3-(5-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-di H-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate CP)

Step 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate. To a solution of 2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethylamine (1 g, 5.34 mmol CAS#932741-19-0) in DCM (15 mL) was added TEA (594 mg, 5.87 mmol) in one portion followed by addition of benzyl chloroformate (1.00 g, 5.87 mmol) to the mixture at 0°C. The mixture was stirred at 0-20°C for 12 h. Upon completion, the mixture was poured into ice water (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over sodium sulfate. Filtering then gave the filtrate and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/1) to give the title compound (1.29 g, 3.83 mmol, 72% yield) as a yellow oil. LC-MS (ESI+) m/z 322.1 (M+H) ⁺ .

Step 2-(2-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate. To a solution of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (2.04 g, _6.02 mmol, intermediate J) and benzyl (2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)carbamate (1.29 g, 4.01 mmol) in THF (7 mL) and ACN (7 mL) were added _Cs2CO3 (7.85 g, 24.08 mmol) and XPhosPd G3 (1.02 g, 1.20 mmol). The mixture was then degassed with nitrogen and heated to 60 ° C, then stirred for 10 h. After completion, the mixture was poured into ice water (10 mL) and extracted with EA (2 × 10 mL). The combined organic phase was washed with brine (2 × 10 mL) and dried over sodium sulfate. The solution was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/0 to 1/4) to give the title compound (1.3 g, 2.04 mmol, 51% yield) as a yellow oil. LC-MS (ESI+) m/z 840.3 (M+H) ⁺ .

Step 3: 3-(5-(3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione. To a solution of benzyl (2-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethoxy)ethyl)carbamate (1.3 g, 2.25 mmol) in THF (10 mL) was added Pd/C (0.2 g, 188.68 μmol, 10 wt%) at 20° C. The mixture was then stirred at 20° C. under hydrogen atmosphere (15 psi) for 13 h. After completion, the mixture was filtered and the filtrate was concentrated to give the title compound (850 mg) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ=7.05-6.98 (m, 2H), 6.89-6.85 (m, 1H), 5.33 (dd, J=5.2, 12.8 Hz, 1H), 3.61-3.59 (m, 1H), 3.55-3.48 (m, 8H), 3.42-3.35 (m, 6H), 3.18-3.05 (m, 1H), 2.95-2.82 (m, 1H), 2.76-2.56 (m, 6H), 1.86-1.72 (m, 4H).

Isopropylcarbamic acid (1S,3R)-3-(1-(tert-butyl)-5-(1-(2-(2-(2-(prop-2-yn-1-yloxy) (Ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate CQ)

A solution of 1-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethyl)-1H-pyrazole-5-carboxylic acid (0.4 g, 1.42 mmol, intermediate BE), (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (743 mg, 2.41 mmol, intermediate CB), T ₃ P (2.71 g, 4.25 mmol, 50% solution in DMF), DIEA (366 mg, 2.83 mmol) in ACN (8 mL) was stirred at 60° C. for 16 h. Upon completion, the mixture was quenched with NH ₄ Cl (saturated aqueous solution, 10 mL) and then extracted with EtOAc (10 mL×2). The combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The crude product was purified by reverse phase (0.1% FA conditions) to afford the title compound (100 mg, 12% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 573.8 (M+H) ⁺ .

3-[(4-Methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (Intermediate CR)

To a solution of hexahydropyrimidine-2,4-dione (3.00 g, 26.2 mmol, CAS#504-07-4) in DMF (60 mL) was added Cs ₂ CO ₃ (17.13 g, 52.58 mmol) at rt. The mixture was then warmed to 50° C., and PMB-Cl (3.71 g, 23.6 mmol) was added dropwise very slowly to the mixture at 50° C. The mixture was stirred at 50° C. for 2 hr. After completion, the reactant was cooled to rt. The mixture was filtered and the filter cake was washed by EA (30 mL×2), the filtrate was poured into water (150 mL) and extracted with EA (100 mL×2). The combined organic layers were washed with water (100 mL) and saturated brine (100 mL), then the organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give a crude product. The crude product was suspended in EA/PE (1/1, 80 mL) and stirred for 0.5 hr. The suspension was filtered and the filter cake was dried to give the title compound as a white solid (2.80 g, 45% yield). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.30 (m, 2H), 6.90-6.62 (m, 2H), 6.15 (s, 1H), 4.88 (s, 2H), 3.78 (s, 3H), 3.37 (dt, J=2.4, 6.8 Hz, 2H), 2.71 (t, J=6.8 Hz, 2H).

3-(4-Methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (Intermediate CS)

To a mixture of dihydropyrimidine-2,4(1H,3H)-dione (10.0 g, 87.6 mmol, CAS#504-07-4) in DMF ( 100 mL) was added PMB-Cl (13.7 g, 87.6 mmol, 11.9 mL), Cs ₂ CO ₃ (28.5 g, 87.6 mmol) at 25° C. The mixture was then stirred at 50° C. for 3 hours. Upon completion, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by recrystallization from EA/PE (20 mL, v/v=1/1) at 25° C. to give the title compound (9.40 g, 45% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.81 (s, 1H), 7.18 (d, J = 8.4Hz, 2H), 6.83 (d, J = 8.4Hz, 2H), 4.72 (s, 2H), 3.72 (s, 3H), 3.23-3.20 (m, 2H), 2.63 (t, J = 6.8Hz, 2H).

4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexanol (Intermediate CT)

Step 1-4-(Hydroxymethyl)cyclohexanol

To a solution of _LiAlH4 (3.31 g, 87.1 mmol) in THF (30 mL) was added a solution of ethyl 4-hydroxycyclohexanecarboxylate (10.0 g, 58.0 mmol, CAS#3618-04-0) in THF (100 mL) dropwise at 0°C, then the mixture was stirred for 5 hr at 0°C. Upon completion, the mixture was quenched with _H2O (3.3 mL), then 15% NaOH solution (3.3 mL) was added dropwise, the mixture was dried _over anhydrous _Na2SO4 , filtered and the filtrate was concentrated in vacuo to give the title compound (7.5 g, 99% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ3.37-3.23(m,1H),3.17(d,J＝6.0Hz,2H),1.85-1.75(m,2H),1.75-1.62(m,2H),1.30-1.16(m,1H),1.14-0.95(m,2H),0.93-0 .72(m,2H).

Step 2-4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexanol

To a solution of 4-(hydroxymethyl)cyclohexanol (6.5 g, 49.9 mmol) and imidazole (4.08 g, 59.9 mmol) in DMF (200 mL) was added TBDPSCl (14.4 g, 52.4 mmol) at 0°C. The mixture was stirred at 25°C for 12 hr. Upon completion, the mixture was diluted with _H2O (100 mL) and extracted with EA (2×30 mL). The organic layer was washed with brine (2×30 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=5:1) to give the title compound (9.10 g, 49% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.70-7.60(m,4H),7.48-7.31(m,6H),3.63-3.51(m,1H),3.47(d,J=6.0Hz,2H),2.05-1.95(m,2H),1.89-1.80(m,2H),1.50-1 .45(m,1H),1.31-1.22(m,2H),1.10-1.00(m,2H),1.05(s,9H).

(4-allyloxycyclohexyl)methoxy-tert-butyl-diphenyl-silane (Intermediate CU)

[0136] To a solution of 4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexanol (500 mg, 1.36 mmol, intermediate CT) in THF (5 mL) was added NaH (81.3 mg, 2.03 mmol, 60% dispersion in mineral oil) at 0°C. After addition, the mixture was stirred at this temperature for 30 minutes before 3-bromoprop-1-ene (656 mg, 5.43 mmol, 0.3 mL, CAS#106-95-6) was added dropwise. The mixture was stirred at 25°C for 4 hr. Upon completion, the mixture was quenched with _H2O (1 mL) at 25°C, diluted with _H2O (10 mL) and extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , DCM:MeOH=10:1) to give the title compound (210 mg, 37% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.59-7.55(m,4H),7.33-7.26(m,6H),5.91-5.78(m,1H),5.22-5.13(m,1H),5.10-5.02(m,1H),3.98-3.89(m,2H),3.37(d,J＝6 .4Hz,2H),3.18-3.08(m,1H),2.01-1.95(m,2H),1.79-1.73(m,2H),1.45-1.41(m,1H),0.96(s,9H),0.93-0.88(m,2H),0.80-0.76(m,2H).

N2-(4-Benzylthio-2-methyl-phenyl)-5-bromo-N4-cyclopentyl-pyrimidine-2,4-diamine (Intermediate CV)

Step 1-5-Bromo-2-chloro-N-4-cyclopentylpyrimidine-4-amine

Cyclopentylamine (4.48 g, 52.6 mmol, CAS#1003-03-8) was added to a solution of 5-bromo-2,4-dichloro-pyrimidine (10 g, 43.8 mmol, CAS#36082-50-5) in dioxane (100 mL) at 0 ° C under a nitrogen stream. The reactant was then stirred for 6 h at 20 ° C under a nitrogen atmosphere. After completion, the reactant was poured into ice water (100 mL) and then extracted with ethyl acetate (150 mL×2). The combined organic phase was washed with brine (70 mL×2), dried over sodium sulfate, then filtered and the filtrate was concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 100: 1 to 100: 15) to give the title compound (4.7 g, 38% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 8.10 (s, 1H), 5.45 (br s, 1H), 4.57-4.29 (m, 1H), 2.20-2.08 (m, 2H), 1.82-1.57 (m, 4H), 1.48 (qd, J = 6.4, 12.8Hz, 2H).

Step 2: N2-(4-(phenylmethylthio)-2-methylphenyl)-5-bromo-N4-cyclopentylpyrimidine-2,4-diamine

To a solution of 5-bromo-2-chloro-N-cyclopentyl-pyrimidin-4-amine (2.65 g, 9.59 mmol) in isopropanol (40 mL) was added 4-benzylsulfanyl-2-methyl-aniline (2 g, 8.72 mmol, intermediate DE) and TFA (19.8 g, 174 mmol) at 20 ° C under a stream of nitrogen. The reactants were then stirred at 80 ° C under a nitrogen atmosphere for 10 h. After completion, the reactants were poured into ice water (40 mL) and extracted with EtOAc (50 mL×2). The combined organic phases were washed with brine (30 mL×2), dried over sodium sulfate, and then the mixture was filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (3.4 g, 83.0% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 11.05 (s, 1H), 7.80 (s, 1H), 7.35-7.23 (m, 6H), 7.20 (d, J = 1.8Hz, 1H), 7.13 (dd, J = 2.0, 8.3Hz, 1H), 5.99 (br d, J = 6.8Hz, 1H), 4.18-4 .06(m,3H),2.28(s,3H),2.00-1.85(m,2H),1.79-1.56(m,4H),1.52-1.44(m,2H).

4-[(6-Chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate CW) and 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methyl Benzene-1-sulfonyl chloride (Intermediate FX)

Step 1-(E)-3-[2-(4-Benzylthio-2-methyl-phenylamino)-4-(cyclopentylamino)pyrimidin-5-yl]propane- 2-enoic acid methyl ester

A mixture of N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-cyclopentyl-pyrimidine-2,4-diamine (10 g, 21.3 mmol, Intermediate CV), prop-2-enoic acid methyl ester (12.6 g, 146 mmol, CAS #96-33-3), TEA (6.47 g, 63.9 mmol) and Pd( _PPh3 ) ₄ (2.46 g, 2.13 mmol) in DMF (200 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 90°C under _N2 atmosphere for 36 hours. Upon completion, the reaction mixture was quenched with _H2O (100 mL) at 25°C and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (FA conditions) to give the title compound (15.6 g, 70% yield) ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.50(s,1H),8.32(s,1H),7.82(d,J＝15.6Hz,1H),7.56(d,J＝8.4Hz,1H),7.34-7.30(m,3H),7.29-7.25(m,3H),7.18(s,1H),7.11(dd,J＝1.6,8.4Hz, 1H), 6.31 (d, J = 15.6Hz, 1H), 4.28-4.23 (m, 1H), 4.18 (s, 2H), 3.69 (s, 3H), 2.19 (s, 3H), 1.88-1.82 (m, 2H), 1.70-1.66 (m, 2H), 1.52-1.46 (m, 4H). LC-MS(ESI ⁺ )m/z 475.2(M+H) ⁺ .

Step 2-2-(4-Benzylthio-2-methyl-phenylamino)-8-cyclopentyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of (E)-3-[2-(4-benzylsulfanyl-2-methyl-phenylamino)-4-(cyclopentylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester (7.8 g, 16.4 mmol) in DMF (80 mL) was added t-BuOK (5.53 g, 49.3 mmol). The mixture was stirred at 25 °C for 30 min. The mixture was then heated to 120 °C and stirred for 1 hr. Upon completion, the reaction mixture was quenched with H ₂ O (200 mL) and extracted with EA (2×300 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=40/1 to 10/1, Rf=0.24) to give the title compound (4.60 g, 63% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 443.0(M+H) ⁺ .

Step 3-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzene Sulfonyl chloride and 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1- Sulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-8-cyclopentyl-pyrido[2,3-d]pyrimidin-7-one (2 g, 4.52 mmol) in ACN (20 mL), AcOH (2 mL) and H ₂ O (0.5 mL) was added NCS (2.41 g, 18 mmol) in the dark. The mixture was stirred at 25° C. in the dark for 0.5 hr. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=40/1 to 10/1, Rf=0.40) to give 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (1.49 g, 72% yield) as a yellow solid ( ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.61(s,1H),8.71(s,1H),8.15(s,1H),7.50(s,1H),7.45-7.35(m,2H),5.71(s,1H),2.22(s,3H),2.15-2.04(m,2H),1.69(s,4H),1.44(s,2H)) and 4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (0.25 g, 12% yield) as a pale yellow solid ( ¹ H NMR (400MHz, CDCl3) δ8.62(s,1H),8.60(s,1H),8.04-7.86(m,2H),7.79(s,1H),7.42(s,1H),5.94(quintet, J=8.7Hz,1H),2.51(s,3H),2.43-2.22(m,2H),2. 18-2.06(m,2H),2.00-1.85(m,2H),1.81-1.56(m,3H); LC-MS(ESI+)m/z 419.1(M+H) ⁺ ).

[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (Intermediate CY)

Step 1-5-Oxotetrahydrofuran-2-carboxylic acid

To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS #617-65-22) in _H2O (800 mL) and HCl (12M, 210 mL) was added a solution of _NaNO2 (147 g, 2.13 mol2) in _H2O (400 _mL ) at -5°C. The mixture was stirred at 15°C for 12 hr. Upon completion, the mixture was concentrated and then dissolved in EA (500 mL) and filtered and washed with EA (3 x 100 mL). The filtrate and washing solution were dried over _Na2SO4 , filtered and concentrated in vacuo to give the title compound as a yellow oil (200 g, crude). ^1H NMR (400 MHz, _CDCl3 ) δ 6.43 (s, 1H), 5.02-4.95 (m, 1H), 2.67-2.38 (m, 4H)

Step 2-N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide

To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol) was added _SOCl2 (246 g, 2.07 mol) slowly at 0°C. The mixture was stirred at 85°C for 3 hrs, and then the mixture was stirred at 15°C for 6 hrs. The mixture was concentrated in vacuo. The residue was dissolved in anhydrous DCM (1 L) at 0°C under _N2 . After that, a solution of _Et3N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was added, and then the mixture was stirred at 15°C for 3 hrs. After completion, water (600 mL) was added and the mixture was extracted with DCM (3 x 300 mL). The combined organic phase was washed with 0.5 M HCl (500 mL), brine (500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.22-7.20 (d, J=8.0, 1H), 6.89-6.87 (d, J=8.0, 1H), 4.90-4.86 (m, 1H), 4.47-4.4.36 (m, 2H) 3.81 (s, 3H), 2.67-2.64 (m, 1H), 2.59-2.54 (m, 2H), 2.40-2.38 (m, 1H); LC-MS (ESI ⁺ ) m/z 272.0 (M+Na) ⁺ .

Step 3-3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione

A solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to -78 ° C. Subsequently, a solution of t-BuOK (62.7 g, 559 mmol) in anhydrous THF (1000 mL) was slowly added dropwise at -78 ° C under a nitrogen atmosphere. The resulting reaction mixture was stirred at -40 ° C for 1 hr. After completion, the reaction mixture was quenched with saturated NH ₄ Cl solution (100 mL). The mixture was extracted with ethyl acetate (3×1500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE: EA=1: 1) to give the title compound (128 g, 92% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.32(m,2H),6.89-6.81(m,2H),4.91(s,2H),4.17-4.11(m,1H),3.80(s,3H),3.54(s,1H),2.98-2.87(m,1H),2.73-2. 60(m,1H),2.26-2.20(m,1H),1.80(dq,J＝4.8,13.1Hz,1H).

Step 4-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate

To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethanesulfonyl triflate (73.0 g, 258 mmol) dropwise at 0°C. The mixture was stirred at -10°C under _N2 for 1.5 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA=20:1/8:1) to give the title compound (45.0 g, 68% yield) as a light yellow gum. ^1. _41-2.35 (m,2H).

5-Bromo-3-methyl-1H-benzimidazol-2-one (Intermediate CZ)

Step 1-5-Bromo-N-methyl-2-nitro-aniline

4-Bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS #321-23-3) was added to a solution of methylamine in tetrahydrofuran (2M, 1.51 L). The mixture was stirred at 15 °C for 10 minutes. Upon completion, the mixture was diluted with _H2O (250 mL) and extracted with EtOAc (3 x 300 mL). The combined organic layers were washed with brine (300 mL), dried _{over Na2SO4} , filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H).

Step 2-4-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 5-bromo-N-methyl-2-nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and H ₂ O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50 °C and then Fe (174 g, 3.11 mol) was added to the reaction mixture. After that, the reaction mixture was stirred at 80 °C for 6 hours. Upon completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was diluted with H ₂ O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with aq. NaHCO ₃ and brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as a black oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 6.55-6.52 (m, 1H), 6.48-6.45 (m, 1H), 6.43-6.42 (m, 1H), 4.89-4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d, J = 4.0Hz, 3H).

Step 3-5-Bromo-3-methyl-1H-benzimidazol-2-one

To a solution of 4-bromo-N2-methyl-benzene-1,2-diamine (110 g, 547 mmol) in CH ₃ CN (1.3 L) was added CDI (177 g, 1.09 mol). The mixture was stirred at 80 °C under N ₂ for 6 h. Upon completion, the mixture was concentrated in vacuo. The mixture was diluted with H ₂ O (1.0 L) and filtered. The filter cake was washed with water (3×200 mL) and dried in vacuo to give the title compound (106 g, 85% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 7.33 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 3.27 (s, 3H).

3-(5-Bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (Intermediate DA)

Step 1-3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidin Pyridine-2,6-dione

To a solution of 5-bromo-3-methyl-1H-benzimidazol-2-one (4.90 g, 21.6 mmol, intermediate CZ) in THF (300 mL) was added t-BuOK (3.63 g, 32.3 mmol) at 0°C. The mixture was stirred at 0-10°C under _N2 for 1 hour. A solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (9.87 g, 25.9 mmol, intermediate CY) in THF (100 mL) was then added to the reaction mixture at 0-10°C over 30 minutes. The mixture was stirred at 0-10°C under _N2 for 30 minutes. An additional solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (2.47 g, 6.47 mmol) in THF (20 mL) was added dropwise to the reaction mixture at 0-10 ° C. The mixture was then stirred for another 30 minutes at 0-10 ° C under N _2. After completion, the reactant was quenched with water (400 mL) and extracted with EA (3×200 mL). The combined organic layers were concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound (6.70 g, 67% yield) as a light yellow solid. The filtrate was also concentrated in vacuo and the residue was purified by column chromatography to give another batch of the title compound (1.80 g, 18% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.47(d,J＝1.6Hz,1H),7.21-7.16(m,3H),7.01(d,J＝8.0Hz,1H),6.85(d,J＝8.8Hz,2H),5.55-5.51(m,1H),4.84-4.73(m,2H),3 .72(s,3H),3.33(s,3H),3.04-3.00(m,1H),2.83-2.67(m,2H),2.07-2.05(m,1H).

Step 2-3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione

To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (8.50 g, 18.6 mmol) in toluene (50 mL) was added methanesulfonic acid (33.8 g, 351 mmol, 25 mL) at room temperature (15 ° C). The mixture was stirred at 120 ° C for 2 hours. After completion, the reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was poured into ice/water (200 mL) and extracted with EA (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with EA (80 mL) and filtered. The filter cake was collected and dried in vacuo to give the title compound (4.20 g, 67% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12(s,1H),7.47(d,J＝2.0Hz,1H),7.22(d,J＝8.4Hz,1H),7.10(d,J＝8.4Hz,1H),5.40-5.35(m,1H),2.34(s,3H),2.92-2.88 (m,1H),2.71-2.60(m,2H),2.03-1.99(m,1H).

3-[3-Methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (Intermediate DB)

Step 1 -4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,6-di Hydrogen-2H-pyridine-1-carboxylic acid tert-butyl ester

To a solution of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine- _2,6 -dione (5.00 g, 14.8 mmol, intermediate DA), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (5.49 g, 17.7 mmol, CAS# 286961-14-6), _K3PO4 (6.28 g, 29.6 mmol) and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (1.16 g, 1.48 mmol) in dioxane (100 mL) and _H2O (5.0 mL) was stirred at 80 °C for 4 hr. After completion, the mixture was filtered and the filtrate was concentrated in vacuo.The residue was purified by reverse phase flash (0.1% FA conditions) to give the title compound (2.30 g, 53% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09 (s, 1H), 7.27 (s, 1H), 7.14-7.04 (m, 2H), 6.11 (s, 1H), 5.36 (dd, J = 12.8, 5.2Hz, 1H), 4.01 (d, J = 7.2Hz, 2H), 3.55 (t, J = 5. 6Hz,2H),3.35(s,3H),2.95-2.83(m,1H),2.73-2.59(m,2H),2.06-1.95(m,2H),1.46-1.39(m,9H),1.17(t,J＝7.2Hz,1H). LC-MS(ESI ⁺ )m/z 441.2(M+H) ⁺ .

Step 2-4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidin-1- Tert-Butyl Formate

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (2.30 g, 5.22 mmol) in THF (150 mL) was added Pd/C (800 mg, 10 wt%) and Pd(OH) ₂ (800 mg, 5.70 mmol) at 25° C. The reaction mixture was stirred at 60° C. under H ₂ (15 psi) for 16 hr. Upon completion, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to give the title compound (2.30 g, 87% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.10(s,1H),7.02-6.87(m,2H),6.76(d,J＝8.0Hz,1H),5.23(dd,J＝5.6,12.6Hz,1H),4.30-4.25(m,2H),3.45(s,3H),2.99-2.68( m,6H),2.30-2.21(m,1H),1.88-1.81(m,2H),1.51(s,9H),1.48-1.44(m,2H). LC-MS(ESI ⁺ )m/z465.2(M+23) ⁺ .

Step 3-3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione

To a mixture of tert _-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidine-1-carboxylate (300 mg, 678 μmol) in DCM (3.0 mL) was added HCl/dioxane (4 M, 170 μL) at 25 °C under N2. The mixture was stirred at 25 °C for 30 min. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (250 mg, 91% yield, HCl salt) as a white solid. LC-MS (ESI ⁺ ) m/z 343.1 (M+H) ⁺ .

3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (intermediate DC

Step 1-2-Bromo-N-methyl-6-nitro-aniline

To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS #58534-94-4) in THF (40 mL) was added _MeNH2 (2M, 400 mL). The reaction mixture was stirred at 60 °C for 12 hours. Upon completion, the reaction mixture was poured into sat. _NaHCO3 (30 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (40.0 g, 95% yield) as a red oil. LC-MS (ESI ⁺ ) m/z 230.9 (M+H) ⁺ .

Step 2-3-Bromo-N2-methyl-benzene-1,2-diamine

To a mixture of 2-bromo-N-methyl-6-nitro-aniline (23.0 g, 99.5 mmol) in EA (300 mL) and H ₂ O (10 mL) was added AcOH (100 mL). The mixture was warmed to 50° C. Then Fe (22.2 g, 398 mmol) was added to the reaction mixture and the mixture was heated to 80° C. for about 4 hours. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EA (3×200 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (20.0 g, 99% yield) as a red oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 6.73-6.70 (m, 1H), 6.68-6.60 (m, 2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58 (s, 3H).

Step 3-4-Bromo-3-methyl-1H-benzimidazol-2-one

To a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4 mmol) in ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reaction mixture was stirred at 85 ° C under _N2 atmosphere for 12 hours. After completion, the reaction mixture was concentrated in vacuo. The reaction mixture was diluted with water (200 mL), where a solid precipitate was formed, which was filtered off. The solid was washed with water (1 L) and dried in vacuo to give the title compound (20.0 g, 88% yield) as a white solid. ¹ H NMR (400 MHz, DMSO- _d6 ) δ 11.17 (s, 1H), 7.14 (dd, J = 1.2, 8.0 Hz, 1H), 7.00-6.95 (m, 1H), 6.93-6.87 (m, 1H), 3.55 (s, 3H).

Step 4-3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidin Pyridine-2,6-dione

To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8 mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reaction mixture was stirred at 0 ° C for 0.5 hr. Afterwards, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (20.1 g, 52.8 mmol, intermediate CY) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at 20 ° C under N ₂ for 0.5 hr. After completion, the reaction mixture was quenched with saturated NH ₄ Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA conditions) to give the title compound (13.3 g, 55% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38 (d, J = 8.8Hz, 2H), 7.22 (d, J = 8.0Hz, 1H), 6.84 (d, J = 8.8Hz, 2H), 6.80 (t, J = 8.0Hz, 1H), 6.48-6.40 (d, J = 8.0Hz, 1H), 5.22 (dd, J = 5. 2,12.8Hz,1H),5.04-4.93(m,2H),3.81(s,3H),3.80(s,3H),3.12-2.98(m,1H),2.93-2.77(m,1H),2.62(dq,J＝4.4,13.2Hz,1H),2.20-2.17(m,1H).

Step 5-3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dihydro- ketone

A mixture of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (13.3 g, 29.0 mmol) in a mixed solvent of Tol. (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with N ₂ three times, and then the mixture was stirred at 120 ° C. under N ₂ atmosphere for 2 hr. After completion, the reaction mixture was concentrated in vacuo to remove toluene. 200 mL of ice water was added to the residue, and then a white solid precipitate was formed. The mixture was filtered and the filter cake was collected and dried in vacuo to give the title compound (7.30 g, 74% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.13(s,1H),7.25(d,J＝8.0Hz,1H),7.17(d,J＝8.0Hz,1H),7.05-6.93(m,1H),5.41(dd,J＝5.2,12.8Hz,1H),3.64(s,3H),2.96- 2.83(m,1H),2.78-2.59(m,2H),2.08-2.00(m,1H).

3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2- 6-Diketone (Intermediate DD)

Step 1-3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl] Piperidine-2,6-dione

To a solution of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (1.00 g, 2.18 mmol, synthesized via step 1-4 of Intermediate DC) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (666 mg, 2.62 mmol, CAS# 173405-78-2) in dioxane (15 mL) was added Pd-PEPPSI-IHEPTCl 3-chloropyridine (212 mg, 218 μmol) and Cs ₂ CO ₃ (1.42 g, 4.36 mmol). The mixture was then stirred at 100 °C for 10 hours. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (400 mg, 29% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ -d) δ7.40-7.35(m,2H),6.93-6.86(m,2H),6.86-6.80(m,2H),6.28(d,J＝7.2Hz,1H),5.21(dd,J＝5.4,13.0Hz,1H),5.02-4.92(m,2H),3.80(s,3H),3. 76(s,3H),3.47-3.39(m,4H),3.04-2.90(m,5H),2.87-2.77(m,1H),2.68-2.55(m,1H),2.18-2.11(m,1H),1.74(s,2H),1.65-1.63(m,4H),1.48(s ,9H),1.43(s,2H). LC-MS(ESI ⁺ )m/z632.4(M+H) ⁺ .

Step 2-3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl] Piperidine-2,6-dione

To a solution of tert-butyl 9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 316 μmol) in TFA (2 mL) was added TfOH (0.2 mL). The mixture was then stirred at 60 °C for 2 hours. Upon completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 90% yield, TFA) as a brown solid. LC-MS (ESI ⁺ ) m/z 412.2 (M+H) ⁺ .

Step 3-9-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-dioxo-3-piperidinyl Azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

To a solution of 3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (150 mg, 285 μmol, TFA) in DCM (4 mL) was added TEA (79.4 μL, 570 μmol) and Boc ₂ O (93.4 mg, 428 μmol), then the mixture was stirred at 25 °C for 10 hours. Upon completion, the mixture was diluted with DCM (100 mL) and extracted with water (50 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (140 mg, 96% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ -d)δ8.46-8.34(m,1H),7.02-6.92(m,2H),6.57(d,J＝7.2Hz,1H),5.22(dd,J＝5.2,12.4Hz,1H),3.99-3.90(m,1H),3.77(s,3H),3.46-3.40(m,4H),2. 97-2.88(m,5 H),2.83(dd,J＝4.8,13.2Hz,1H),2.77-2.73(m,J＝4.0,15.2Hz,1H),2.22-2.16(m,J＝2.8,5.2,10.8Hz,1H),1.74(s,3H),1.65-1.63(m,J＝8.0Hz,4H),1. 48(s,9H). LC-MS(ESI ⁺ )m/z 512.4(M+H) ⁺ .

Step 4-3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl] Piperidine-2,6-dione

To a solution of tert-butyl 9-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (50.0 mg, 97.7 μmol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (40.0 mg, 99% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 412.1 (M+H) ⁺ .

4-Benzylthio-2-methyl-aniline (Intermediate DE)

Step-1-4-Benzylthio-2-methyl-1-nitro-benzene

A mixture of 4-fluoro-2-methyl-1-nitro-benzene (20.0 g, 128 mmol, CAS #446-33-3), BnSH (18.1 mL, 154 mmol), and DIEA (33.3 g, 257 mmol, 44.9 mL) in DMF (200 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 80 ° C under N ₂ atmosphere for 16 hours. Upon completion, the reaction mixture was quenched with NaClO (10 mL) at 25 ° C, and then diluted with H ₂ O (10 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (26.0 g, 76% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (d, J=4.0 Hz, 1H) 7.51-7.37 (m, 5H) 7.30-7.25 (m, 2H) 4.34 (s, 2H) 2.69 (s, 3H). LC-MS (ESI ⁺ ) m/z 260.0 (M+H) ⁺ .

Step-2-4-Benzylthio-2-methyl-aniline

A mixture of 4-benzylsulfanyl-2-methyl-1-nitro-benzene (18.0 g, 69.4 mmol), Fe (23.2 g, 416 mmol), NH ₄ Cl (37.1 g, 694 mmol) in EtOH (180 mL) and H ₂ O (36 mL) was degassed and purged with N ₂ three times. , and then the mixture was stirred at 80 ° C under N ₂ atmosphere for 1.5 hours. After completion, the reaction mixture was diluted with H ₂ O 100 mL and extracted with EA (60 mL×3). The combined organic layers were washed with brine (40 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (63 g, 98% yield) as a black oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.29-7.18 (m, 5H) 6.99 (s, 1H) 6.93 (d, J = 1.6 Hz, 1H) 6.57 (d, J = 8.0 Hz, 1H) 4.99 (s, 2H) 3.96 (s, 2H) 2.03 (s, 3H).

5-Bromo-2-chloro-N-isopropyl-pyrimidin-4-amine (Intermediate DF)

To a solution of 5-bromo-2,4-dichloro-pyrimidine (10.0 g, 43.8 mmol, 5.62 mL, CAS #36082-50-5) in ACN (250 mL) was added TEA (5.77 g, 57.0 mmol, 7.94 mL) and propan-2-amine (3.37 g, 57.0 mmol, 4.90 mL) at 0 °C for 30 min. The mixture was then stirred at 25 °C for 15.5 hours. Upon completion, the reaction mixture was diluted with H ₂ O (200 mL) and extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (10 g, 90% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 251.8 (M+H) ⁺ .

4-[(6-Chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (Intermediate DG)

Step 1 - N2-(4-Benzylthio-2-methyl-phenyl)-5-bromo-N4-isopropyl-pyrimidine-2,4-diamine

To a solution of 4-benzylsulfanyl-2-methyl-aniline (1.00 g, 4.36 mmol, intermediate DE) in IPA (10 mL) was added 5-bromo-2-chloro-N-isopropyl-pyrimidin-4-amine (1.20 g, 4.80 mmol, intermediate DF) and TFA (9.94 g, 87.2 mmol, 6.46 mL) at 20 °C under a stream of nitrogen. The reaction was then stirred at 80 °C under nitrogen atmosphere for 20 hr. Upon completion, the mixture was diluted with _H2O (20 mL) and extracted with EA (30 mL x 3). The combined organic layers were washed with _NaHCO3 (30 mL), then with brine (30 mL x 3 ₎ , dried over anhydrous _Na2SO4 , filtered and the filtrate concentrated in vacuo. The mixture was purified by pre-HPLC (column: Phenomenex luna C18 250*50mm*15μm; mobile phase: [water(FA)-ACN]; B%: 23%-53%, 20min) to give the title compound (600mg, 31% yield) as a black solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.25 (s, 1H), 7.91 (s, 1H), 7.47 (d, J = 8.4Hz, 1H), 7.36-7.25 (m, 4H), 7.23 (d, J = 6.8Hz, 1H), 7.16 (s, 1H), 7.09 (d, J = 8.4Hz, 1H) ,6.33(d,J＝8.0Hz,1H),4.17(s,3H),2.16(s,3H),1.15(d,J＝6.4Hz,6H). LC-MS(ESI ⁺ )m/z 444.9(M+H) ⁺ .

Step 2-(E)-3-[2-(4-Benzylthio-2-methyl-phenylamino)-4-(isopropylamino)pyrimidin-5-yl]propane- 2-enoic acid methyl ester

To a mixture of N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-isopropyl-pyrimidine-2,4-diamine (2.20 g, 4.96 mmol), TEA (1.51 g, 14.8 mmol, 2.07 mL) and Pd(PPh ₃ ) ₄ (1.15 g, 992 μmol) in DMF (25 mL) was added prop-2-enoic acid methyl ester (3.11 g, 36.1 mmol, 3.25 mL). The mixture was degassed and purged with N ₂ three times, and then the mixture was stirred at 90 ° C under N ₂ atmosphere for 16 hours. After completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 ° C, and then extracted with EA (20 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 5/1) (Rf=0.5, PE:EA=2:1) to give the title compound (1.3 g, 58% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 8.31 (s, 1H), 7.78 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.37-7.08 (m, 9H), 6.31 (d, J=15.2 Hz, 1H), 4.18 (s, 2H), 3.68 (s, 3H), 2.18 (s, 3H), 1.16-1.10 (m, 6H). LC-MS (ESI ⁺ ) m/z 449.5 (M+H) ⁺ .

Step 3-2-(4-Benzylthio-2-methyl-phenylamino)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of (E)-3-[2-(4-benzylsulfanyl-2-methyl-phenylamino)-4-(isopropylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester (110 mg, 245 μmol) in DMF (2 mL) was added t-BuOK (82.5 mg, 735 μmol). The mixture was stirred at 25 °C for 30 min. The mixture was then heated to 120 °C and stirred for 1 hr. After completion, the mixture was concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , PE:EA=1:1) (Rf=0.5, PE:EA=1:1) to give the title compound (50 mg, 48% yield) as a yellow solid. ² .17(s,3H),1.34(d,J=5.2Hz _, 6H). LC-MS(ESI ⁺ )m/z 867.3(M+H) ⁺ .

Step 4-4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzene Sulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 240 μmol) in ACN (1 mL), AcOH (0.1 mL), H ₂ O (0.01 mL) was added NCS (128 mg, 960 μmol). The mixture was stirred at 25° C. in the dark for 16 hr. Upon completion, the mixture was quenched with H ₂ O (5 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by prep-TLC (SiO ₂ , PE:EA＝1:1) (Rf＝0.56, PE:EA＝1:1) to give the title compound (35 mg, 34% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 426.8(M+H) ⁺ .

3-[3-methyl-2-oxo-5-(4-oxo-1-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (intermediate DH)

Step 1-3-[5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methyl-2-oxo-benzimidazole- 1-yl]piperidin-2,6-dione

To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (635 mg, 4.44 mmol, CAS# 177-11-7) in toluene (10 mL) was added LiHMDS (1 M, 17.7 mL) and the mixture was then stirred at 110 °C for 30 minutes. Then, 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (1 g, 2.96 mmol, intermediate DA), RuPhos Pd G3 (494 mg, 591 μmol) and RuPhos (275 mg, 591 μmol) were added and the mixture was stirred at 110 °C for 1.5 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound as a grey solid (500 mg, 42% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.05 (s, 1H), 6.96-6.82 (m, 2H), 6.65 (d, J = 8.4Hz, 1H), 3.91 (s, 4H), 3.23-3.14 (m, 5H), 2.95-2.83 (m, 2H), 2.73-2.58 (m, 3 H),2.07(s,1H),2.03-1.94(m,1H),1.78-1.70(m,4H). LC-MS(ESI ⁺ )m/z 401.0(M+H) ⁺ .

Step 2-3-[3-methyl-2-oxo-5-(4-oxo-1-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione

A mixture of 3-[5-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (100 mg, 249 μmol) in HCOOH (12.0 mg) was stirred at 80° C. for 12 hr. After completion, the reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (80 mg, 80% yield). LC-MS (ESI ⁺ ) m/z 537.1 (M+H) ⁺ .

4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperidin (4-(2-oxazin-1-ylpropyl)benzenesulfonamide (Intermediate DI)

Step 1-4-[3-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3- Methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (68.3 mg, 280 μmol, CAS# 373608-48-1) in DMF (1 mL) was added DIEA (90.7 mg, 702 μmol) followed by 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (100 mg, 234 μmol, Intermediate DG). The mixture was stirred at 25 °C for 10 min. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (100 mg, 67% yield) as a grey oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.65(s,1H),8.81-8.63(m,1H),8.25-8.08(m,1H),7.85-7.71(m,3H),7.69-7.57(m,2H),7.53-7.37(m,2H),2.37-2.33(m, 3H), 2.07 (d, J＝2.0Hz, 1H), 1.77-1.64 (m, 2H), 1.39 (d, J＝1.6Hz, 9H), 1.27 (s, 6H), LC-MS (ESI ⁺ ) m/z 633.9 (M+H) ⁺ .

Step 2-4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N- (3-Piperazin-1-ylpropyl)benzenesulfonamide

To a solution of tert-butyl 4-[3-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylate (50 mg, 78.8 μmol) in DCM (1 mL) was added TFA (770 mg) and the mixture was then stirred at 25 °C for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound as a light yellow oil (50 mg, 97% yield). LC-MS (ESI ⁺ ) m/z 534.1 (M+H) ⁺ .

tert-Butyl 4-But-3-enylpiperazine-1-carboxylate (Intermediate DJ)

To a solution of 4-bromobut-1-ene (2.83 g, 20.9 mmol, CAS#5162-44-7) and tert-butyl piperazine-1-carboxylate hydrochloride (3.00 g, 13.4 mmol, CAS#57260-71-6) in THF (100 mL) was added K ₂ CO ₃ (6.69 g, 48.4 mmol) and TBAI (300 mg, 812 μmol). The mixture was then stirred at 70 °C for 15 hr. After completion, the mixture was filtered, diluted with water (100 mL) and extracted with EA (30 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=15:1 to 1:1) to give the title compound (1.50 g, 46% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 5.86-5.76 (m, 1H), 5.09-5.00 (m, 2H), 3.48-3.40 (m, 4H), 2.45-2.39 (m, 6H), 2.28-2.23 (m, 2H), 1.47 (s, 9H). LC-MS(ESI ⁺ )m/z 241.1(M+H) ⁺ .

4-(1,3-Dioxolan-2-yl)piperidine (Intermediate DL)

Step 1-4-(1,3-dioxolan-2-yl)piperidine-1-carboxylic acid benzyl ester

A solution of benzyl 4-formylpiperidine-1-carboxylate (20.0 g, 80.9 mmol, CAS#138163-08-3), PTSA (1.4 g, 8.09 μmol) and ethylene glycol (5.52 g, 88.9 mmol, CAS#107-21-1) in toluene (200 mL) was refluxed at 130° C. for 16 hr. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 0/1) to give the title compound (15.0 g, 63% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ7.43-7.28(m,5H),5.13(s,2H),4.65(d,J＝4.4Hz,1H),4.24(s,2H),3.99-3.82(m,4H),2.77(s,2H),1.85-1.64(m,3H),1.42-1. 26(m,2H).

Step 2-4-(1,3-dioxolan-2-yl)piperidine

To a solution of benzyl 4-(1,3-dioxolan-2-yl)piperidine-1-carboxylate (5 g, 20 mmol) in MeOH (100 mL) was added Pd/C (1.5 g, 1.4 mmol, 10 wt%) _under N. The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred at 25 °C under _H (15 PSI) for 4 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (2.3 g, 85% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ4.62(d,J＝4.8Hz,1H),3.98-3.81(m,4H),3.11(d,J＝12.0Hz,2H),2.60(m,2H),1.98(s,1H),1.73(d,J＝14.4Hz,2H),1.69-1.62(m ,1H),1.38-1.24(m,2H).

1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]piperidine-4-carboxaldehyde (Medium Intermediate DM)

Step 1-3-[5-[4-(1,3-dioxolan-2-yl)-1-piperidinyl]-3-methyl-2-oxo-benzimidazole-1- 1-[4-[[(4-[[[[piperidin-2,6-dione] ...

To a solution of 4-(1,3-dioxolan-2-yl)piperidine (500 mg, 3.18 mmol, intermediate DL) and 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (1.08 g, 3.18 mmol, intermediate DA) in toluene (15 mL) was added RuPhos (148 mg, 318 μmol), RuPhos Pd G ₃ (266 mg, 318 μmol) and LiHMDS (1 M, 19.0 mL). Upon completion, the reaction mixture was acidified to pH=7 by HCOOH and concentrated in vacuo. The residue was triturated with PE/EA (3/1), filtered and the filter cake was triturated with water. The solid was filtered and dried in vacuo to give the title compound as a grey solid (1.1 g, 83% yield). ¹ HNMR (400 MHz, DMSO-d ₆ )δ11.05(s,1H),6.92(d,J＝8.4Hz,1H),6.82(d,J＝2.0Hz,1H),6.63(dd,J＝2.0,8.4Hz,1H),5.28(dd,J＝5.2,12.8Hz,1H),4.61(d,J＝5.2Hz,1H),3.93-3.75( m,4H),3.62(d,J＝1 2.4Hz,2H),3.37-3.30(m,3H),2.95-2.82(m,1H),2.67(dd,J＝4.4,12.8Hz,1H),2.63-2.55(m,3H),2.02-1.93(m,1H),1.78-1.72(m,2H),1.65-1.56 (m,1H),1.50-1.39(m,2H).

Step 2-1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidin-4-yl formaldehyde

A solution of 3-[5-[4-(1,3-dioxolan-2-yl)-1-piperidinyl]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (100 mg, 241 μmol) in HCOOH (3 mL) was stirred at 50° C. for 3 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (89 mg, 99% yield) as a brown oil. LCMS (ESI ⁺ ) m/z 371.0 (M+H) ⁺ .

8-Isopropyl-2-methylthio-pyrido[2,3-d]pyrimidin-7-one (Intermediate DN)

Step 1-5-Bromo-N-isopropyl-2-methylsulfanyl-pyrimidin-4-amine

To a solution of 5-bromo-2-chloro-N-isopropyl-pyrimidin-4-amine (10.0 g, 39.9 mmol, intermediate DF) in DMF (110 mL) was added NaSMe (7.12 g, 101 mmol, 6.47 mL). The mixture was stirred at 25 °C under _N2 for 16 hr. Upon completion, the reaction mixture was quenched with _H2O (100 mL) at 25 °C and then extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (9.50 g, 90% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.95 (s, 1H), 4.32-4.25 (m, 1H), 2.89 (s, 3H), 2.73 (s, 3H), 2.41 (s, 3H). LC-MS(ESI ⁺ )m/z 263.8(M+H) ⁺ .

Step 2-(E)-3-[4-(Isopropylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoic acid methyl ester

A mixture of 5-bromo-N-isopropyl-2-methylsulfanyl-pyrimidin-4-amine (9.50 g, 36.2 mmol), prop-2-enoic acid methyl ester (22.3 g, 259 mmol, 23.3 mL, CAS #96-33-3), Pd(PPh ₃ ) ₄ (4.19 g, 3.62 mmol) and TEA (11.0 g, 108 mmol, 15.0 mL) in DMF (100 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 90 ° C under N ₂ atmosphere for 32 hr. After completion, the reaction mixture was quenched with H ₂ O (100 mL) at 25 ° C, and then extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) (Rf=0.40, PE:EA=1:1) to give the title compound (5.80 g, 59% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.43-8.30 (m, 1H), 7.79 (d, J=15.6 Hz, 1H), 7.49 (d, J=7.2 Hz, 1H), 6.55-6.43 (m, 1H), 4.35 (d, J=6.8, 13.4 Hz, 1H), 3.71 (s, 3H), 2.44 (s, 3H), 1.19 (d, J=6.4 Hz, 6H). LC-MS (ESI ⁺ ) m/z 268.1 (M+H) ⁺ .

Step 3-8-Isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

A mixture of (E)-3-[4-(isopropylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoic acid methyl ester (5.73 g, 21.4 mmol), DBU (16.3 _{g, 107 mmol, 16.1 mL) in NMP (50.0 mL) was degassed and purged with N 3 times. The mixture was then stirred at 120 °C under N 2 atmosphere} for 1 hr. Upon completion, the mixture was diluted with H ₂ O (300 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×100 mL), then dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (4.20 g, 83% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.84 (s, 1H), 7.86 (d, J = 9.6 Hz, 1H), 6.56 (d, J = 9.6 Hz, 1H), 5.75-5.56 (m, 1H), 2.59 (s, 3H), 1.53 (d, J = 6.8 Hz, 6H). LC-MS(ESI ⁺ )m/z 236.1(M+H) ⁺ .

4-[[6-(Difluoromethyl)-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl- Benzenesulfonyl chloride (intermediate DO)

Step 1-6-[Chloro(difluoro)methyl]-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a 15 mL vial equipped with a stir bar was added 4-phenylpyridine N-oxide (3.64 g, 21.0 mmol), 8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 8.50 mmol, intermediate DN), and Ru(bpy) ₃ Cl ₂ .6H ₂ O (63.6 mg, 85.0 μmol) in anhydrous ACN (20 mL) followed by (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (5.16 g, 21.0 mmol, CAS# 2834-28-3). The vial was sealed and placed under added nitrogen. The reaction was stirred and irradiated with a 34 W blue LED lamp (2 cm away) while the reaction temperature was maintained at 25° C. for 16 hr with cooling water. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 10/1) (Rf=0.55, PE:EA=1:1) to give the title compound (1.37 g, 50% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.02 (s, 1H), 8.50 (s, 1H), 5.82-5.64 (m, 1H), 2.63 (s, 3H), 1.57 (d, J=6.8 Hz, 6H). LC-MS (ESI ⁺ ) m/z 319.6 (M+H) ⁺ .

Step 2-6-(Difluoromethyl)-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

A mixture of 6-[chloro(difluoro)methyl]-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (200 mg, 625 μmol), Pd/C (10.0 mg, 6.25 μmol, 10 wt%), Na ₂ CO ₃ (99.0 mg, 938 μmol) in THF (2 mL) was degassed and purged with H ₂ three times. The mixture was then stirred at 25 °C under H ₂ atmosphere for 2 hours. After completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1 to 10/1) (Rf=0.70, PE:EA=3:1) to give the title compound (70.0 mg, 39% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.28 (s, 1H), 5.87-5.59 (m, 1H), 3.36-3.26 (m, 1H), 2.62 (s, 3H), 1.56 (d, J = 6.8Hz, 6H). LC-MS(ESI ⁺ )m/z 286.0(M+H) ⁺ .

Step 3-6-(Difluoromethyl)-8-isopropyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-(difluoromethyl)-8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (260 mg, 911 μmol) in DCM (2 mL) was added m-CPBA (740 mg, 3.65 mmol, 85% solution). The mixture was stirred at 40 ° C for 3 hr. After completion, the mixture was quenched with NaHCO ₃ (10 mL) and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=30/1 to 10/1) to give the title compound (100 mg, 34% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 317.9 (M+H) ⁺ .

Step 4-2-(4-Benzylthio-2-methyl-phenylamino)-6-(difluoromethyl)-8-isopropyl-pyrido[2, 3-d]pyrimidin-7-one

A mixture of 6-(difluoromethyl)-8-isopropyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one (70.0 mg, 220 μmol), 4-benzylsulfanyl-2-methyl-aniline (151 mg, 661 μmol, intermediate DE), TFA (251 mg, 2.21 mmol, 163 μL) in IPA (2 mL) was added, and then the mixture was stirred at 90 ° C for 5 hr. After completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (27.0 mg, 26% yield) as a brown oily liquid. ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.56 (s, 1H), 8.81 (s, 1H), 8.10 (s, 1H), 7.37-7.17 (m, 8H), 6.88 (t, J = 56.0Hz, 1H), 5.59-5.37 (m, 1H), 4.23 (s, 2H), 2.17 (s, 3H ),1.34(s,6H). LC-MS(ESI ⁺ )m/z467.2(M+H) ⁺ .

Step 5-4-[[6-(Difluoromethyl)-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]- 3-Methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-6-(difluoromethyl)-8-isopropyl-pyrido[2,3-d]pyrimidin-7-one (22.0 mg, 47.1 μmol) in ACN (1 mL), AcOH (0.1 mL) and H ₂ O (0.01 mL) was added NCS (16.0 mg, 126 μmol). The mixture was stirred at 25 °C in the dark for 1 hr. Upon completion, the mixture was diluted with H ₂ O (10 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give the title compound (20.0 mg, 95% yield) as a brown oily liquid. LC-MS (ESI ⁺ ) m/z 442.9 (M+H) ⁺ .

Tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate (Intermediate DP)

Step 1-ethyl 2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]acetate

To a solution of 4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexanol (8.60 g, 23.3 mmol, intermediate CT) and _Rh2 (OAc) ₄ (1.03 g, 2.33 mmol) in DCM (40 mL) was added a solution of ethyl 2-diazoacetate (10.6 g, 93.3 mmol) in DCM (40 mL). The mixture was degassed and purged with _N2 three times and the mixture was stirred at 25 °C under _N2 atmosphere for 12 hr. Upon completion, the mixture was diluted with DCM (80 mL), the organic layer was washed with _H2O (2×80 mL), brine (2×80 mL ₎ , dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=10:1) to give the title compound (10.0 g, 94% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.72-7.61(m,4H),7.48-7.32(m,6H),4.28-4.25(m,2H),4.12(s,2H),3.46(d,J=6.0Hz,2H),3.32-3.22(m,1H),2.15-2.04(m, 2H),1.91-1.81(m,2H),1.54-1.45(m,1H),1.32-1.28(m,5H),1.09-0.99(m,2H),1.05(s,9H).

Step 2-2-[4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]ethanol

To a solution of LAH (626 mg, 16.5 mmol) in THF (25 mL) was added a solution of ethyl 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]acetate (5.00 g, 11.0 mmol) in THF (25 mL) dropwise at 0°C. The mixture was stirred at 0°C for 0.5 hr. Upon completion, the mixture was quenched with _H2O (0.62 mL) followed by the dropwise addition of 15% NaOH solution (0.62 mL). _The mixture was dried over anhydrous _Na2SO4 , filtered and the filtrate concentrated in vacuo to give the title compound (3.15 g, 69% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.76-7.61(m,4H),7.49-7.33(m,6H),3.81-3.66(m,3H),3.63-3.57(m,2H),3.50-3.45(m,2H),3.28-3.18(m,1H),2.15-2.0 4(m,2H),1.88-1.83(m,2H),1.61-1.46(m,1H),1.28-1.20(m,2H),1.10-0.96(m,2H),1.05(s,9H).

Step 3-2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]ethyl 4-methylbenzenesulfonate

To a solution of 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethanol (3.15 g, 7.63 mmol) in DCM (40 mL) was added TEA (1.13 g, 11.1 mmol), DMAP (170 mg, 1.39 mmol) and TosCl (1.59 g, 8.35 mmol). The mixture was stirred at 25 °C for 16 hr. After completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=10:1) to give the title compound (2.86 g, 90% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.88-7.76(m,2H),7.68-7.60(m,4H),7.44-7.31(m,8H),4.19-4.12(m,2H),3.72-3.62(m,2H),3.45(d,J＝6.4Hz,2H),3.19-3.0 6(m,1H),2.45(s,3H),2.00-1.90(m,2H),1.88-1.75(m,2H),1.52-1.42(m,1H),1.20-1.10(m,2H),1.05(s,9H),1.01-0.92(m,2H).

Step 4-2-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]ethyl]isoindoline- 1,3-Dione

To a solution of 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl 4-methylbenzenesulfonate (2.86 g, 5.05 mmol) in DMF (20 mL) was added potassium (1,3-dioxoisoindolin-2-yl) (1.40 g, 7.57 mmol). The mixture was stirred at 50 °C for 5 hr. Upon completion, the mixture was diluted with _H2O (150 mL) and extracted with EA (3 x 50 mL). The organic layer was washed with brine (3 x 40 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (2.7 g, 98% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.89-7.83(m,2H),7.74-7.69(m,2H),7.68-7.61(m,4H),7.45-7.34(m,6H),3.95-3.82(m,2H),3.77-3.68(m,2H),3.44(d,J＝6 .1Hz,2H),3.28-3.15(m,1H),2.03-1.94(m,2H),1.87-1.75(m,2H),1.54-1.40(m,1H),1.22-1.12(m,2H),1.04(s,9H),1.02-0.90(m,2H).

Step 5-2-[4-[[tert-Butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]ethylamine

To a solution of 2-[2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl]isoindoline-1,3-dione (2.7 g, 4.98 mmol) in EtOH (20 mL) was added NH ₂ NH ₂ .H ₂ O (3.19 g, 54.1 mmol, 3.10 mL, 85% solution). The mixture was stirred at 50 °C for 2 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was diluted with DCM (30 mL) and filtered, and the filtrate was concentrated in vacuo to give the title compound (2.02 g, 98% yield) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ7.70-7.63(m,4H),7.47-7.35(m,6H),3.54(t,J＝4.8Hz,2H),3.47(d,J＝6.0Hz,2H),3.25-3.15(m,1H),2.90(t,J＝5.2Hz,2H),2. 33-2.19(m,2H),2.13-2.00(m,2H),1.88-1.78(m,2H),1.56-1.45(m,1H),1.28-1.20(m,2H),1.06(s,9H),1.04-0.94(m,2H).

Step 6 - N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]ethyl]carbamic acid Tert-butyl ester

To a solution of 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethanamine (2 g, 5 mmol) in DCM (20 mL) was added TEA (983 mg, 9.72 mmol, 1.35 mL) and (Boc) ₂ O (1.27 g, 5.83 mmol, 1.34 mL). The mixture was stirred at 25 °C for 3 hr. After completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=10:1) to give the title compound (1.88 g, 75% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.77-7.58 (m, 4H), 7.53-7.32 (m, 6H), 5.00-4.79 (m, 1H), 3.53 (t, J = 5.2Hz, 2H), 3.47 (d, J = 6.0Hz, 2H), 3.33-3.25 (m, 2H), 3.22-3 .12(m,1H),2.10-1.99(m,2H),1.89-1.80(m,2H),1.54-1.46(m,1H),1.49(s,9H),1.27-1.15(m,2H),1.06(s,9H),1.05-0.93(m,2H).

Step 7 - tert-Butyl N-[2-[4-(Hydroxymethyl)cyclohexyloxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl]carbamate (1.78 g, 3.48 mmol) in THF (15 mL) was added TBAF (1.00 M, 5.22 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo and then purified by silica gel column (PE:EA=1:1) to give the title compound (950 mg, 99% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ5.00-4.75(m,1H),3.53(t,J＝5.2Hz,2H),3.47(d,J＝6.4Hz,2H),3.34-3.26(m,2H),3.25-3.13(m,1H),2.13-2.03(m,2H),1.90 -1.80(m,2H),1.56-1.50(m,1H),1.46(s,9H),1.30-1.16(m,3H),1.05-0.91(m,2H).

Step 8 - tert-Butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate

To a solution of tert-butyl N-[2-[4-(hydroxymethyl)cyclohexyloxy]ethyl]carbamate (800 mg, 2.93 mmol) in DCM (20 mL) was added DMP (1.49 g, 3.51 mmol). The mixture was stirred at 25 ° _C for 0.5 hr. Upon completion, the mixture was diluted with DCM (100 mL) and quenched with saturated _Na2S2O3 (50 mL), and washed with saturated _NaHCO3 (3 _{x 50} mL). The organic layer was dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (790 mg, 99% yield) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ9.65 (d, J = 1.2Hz, 1H), 5.05-4.67 (m, 1H), 3.57-3.49 (m, 2H), 3.37-3.17 (m, 3H), 2.17-1.99 (m, 4H), 1.46 (s, 10H), 1.41-1.23 (m, 4H)

3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidinyl]-3-methyl-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate DQ)

Step 1-N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5- tert-butyl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]carbamate

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (756 mg, 1.66 mmol, TFA, intermediate DB), tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate (500 mg, 1.84 mmol, intermediate DP) in DMF (4 mL) and THF (16 mL) was added TEA (372 mg, 3.69 mmol). The mixture was stirred at -10 °C for 0.5 h. HOAc (331 mg, 5.53 mmol, 316 μL) was then added, and the mixture was stirred at -10 °C for 0.5 hr. NaBH(OAc) ₃ (781 mg, 3.69 mmol) was then added, and the mixture was stirred at -10 °C for 1 hr. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% FA) to give the title compound (630 mg, 57% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.08 (s, 1H), 7.07 (s, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 6.79-6.67 (m, 1H), 5.37-3.29 (m, 1H), 3.33 (s, 3H), 3.27-3.12 (m, 7H), 3.05-3.02 (m, 2H), 2.95- 2.82(m,2H),2.74-2.66(m,2H),2.64-2.55(m,2H),2.06-1.94(m,3H),1.90-1.70(m,6H),1.67-1.53(m,1H),1.37(s,9H),1.18-1.07(m,2H),1.0 3-0.86(m,2H),LC-MS(ESI ⁺ )m/z 598.3(M+H) ⁺ .

Step 2-3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidinyl]-3-methyl-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]carbamate (530 mg, 886 μmol) in DCM (8 mL) was added TFA (2.04 g, 17.9 mmol, 1.32 mL). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (530 mg, 97% yield, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 498.2 (M+H) ⁺ .

Tert-butyl N-[4-(4-piperidinyl)butyl]carbamate (Intermediate DR)

Step 1 - tert-Butyl N-[4-(4-pyridyl)butyl]carbamate

A mixture of tert-butyl N-(4-bromobutyl)carbamate (50.4 mg, 0.2 mmol, 41.0 μL, CAS#164365-88-2) and 4-bromopyridine (24.3 mg, 153 μmol, CAS#1120-87-2) in ACN (1 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 25 ° C under N ₂ atmosphere for 12 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*10μm; mobile phase: [water (FA)-ACN]; B%: 35%-50%, 30min) to give the title compound (400 mg, 26% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.49(d,J＝4.4Hz,2H),7.12(d,J＝4.0Hz,2H),4.53(s,1H),3.15(d,J＝6.4Hz,2H),2.64(t,J＝7.6Hz,2H),1.72-1.62(m,2H),1.57- 1.50(m,2H),1.44(s,9H). LC-MS(ESI ⁺ )m/z 251.1(M+H) ⁺ .

Step 2 - tert-Butyl N-[4-(4-piperidinyl)butyl]carbamate

To a solution of tert _-butyl N-[4-(4-pyridinyl)butyl]carbamate (400 mg, 1.60 mmol) in EtOH (5 mL) was added _PtO (362 mg, 1.60 mmol) and HOAc (95.9 mg, 1.60 mmol, 92.0 μL) under N. The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred under _H (15 psi) at 25 °C for 12 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (500 mg, 98% yield, HOAc salt) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.56 (s, 1H), 3.38 (d, J = 12.4Hz, 2H), 3.11 (d, J = 5.6Hz, 2H), 2.82 (t, J = 11.6Hz, 2H), 1.83 (d, J = 11.6Hz, 2H), 1.44 (s, 15H), 1.32 (s, 4 H). LC-MS(ESI ⁺ )m/z 257.3(M+H) ⁺ .

1-(4-Bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (Intermediate DS)

To a solution of 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (2 g, 9 mmol, CAS#589-87-8) and 1-bromo-4-iodo-benzene (2.68 g, 9.49 mmol, CAS#504-07-4) in DMF (30 mL) was added DBU (2.89 g, 18.9 mmol) and CuI (1.81 g, 9.49 mmol). The mixture was stirred at 140 °C for 16 hr. After completion, the reaction mixture was filtered and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give the title compound (2.5 g, 68% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 390.7(M+H) ⁺ .

1-[4-[4-(4-aminobutyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate DT)

Step 1 - N-[4-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]benzene tert-Butyl]-4-piperidinyl]butyl]carbamate

A mixture of tert-butyl N-[4-(4-piperidinyl)butyl]carbamate (280 mg, 1.09 mmol, Intermediate DR), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (100 mg, 256 μmol, Intermediate DS), Cs ₂ CO ₃ (502 mg, 1.54 mmol), and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (22.1 mg, 25.6 μmol) in dioxane (1 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 °C under N ₂ atmosphere for 12 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water(FA)-ACN]; B%: 38%-68%, 10min) to give the title compound (200mg, 66% yield) as a white solid. ^1H NMR (400MHz, CDCl ₃ )δ7.46-7.38(m,2H),7.16-7.05(m,2H),6.92(d,J＝8.8Hz,2H),6.86-6.79(m,2H),4.95(s,2H),4.54(s,1H),3.78(s,3H),3.71(t,J＝6.8Hz,2H),3.6 4(d,J＝12.4Hz,2H),3.17-3.07(m,2H),2.84(t,J＝6.8Hz,2H),2.68(t,J＝11.6Hz,2H),1.77(d,J＝10.4Hz,2H),1.53-1.47(m,2H),1.45(s,9H),1.40-1. 26(m,7H). LC-MS(ESI ⁺ )m/z 565.3(M+H) ⁺ .

Step 2-1-[4-[4-(4-aminobutyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione

A mixture of tert-butyl N-[4-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]butyl]carbamate (100 mg, 177 μmol) and TfOH (26.5 mg, 177 μmol, 15.6 μL) in TFA (1.2 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 70 ° C under N ₂ atmosphere for 1 hr. After completion, the mixture was concentrated under reduced pressure to give the title compound (61 mg, 76% yield, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 345.0 (M+H) ⁺ .

tert-Butyl N-[5-(4-piperidinyl)pentyl]carbamate (Intermediate DU)

Step 1 - tert-Butyl N-[5-(4-pyridyl)pentyl]carbamate

To a vial equipped with a stir bar was added 4-bromopyridine (1.00 g, 6.33 mmol, CAS#1120-87-2), tert-butyl N-(5-bromopentyl)carbamate (2.19 g, 8.23 mmol, CAS#83948-54-3), Ir[dF( _CF3 )ppy] ₂ (dtbpy)( _PF6 ) (71.0 mg, 63.2 _μmol ), _NiCl2.dtbbpy (37.7 mg, 94.9 μmol), TTMSS (1.57 g, 6.33 mmol), and _Na2CO3 (1.34 g, 12.6 mmol) in DME (10 mL). The vial was sealed and placed under added nitrogen. The reaction was stirred and irradiated with a 10 W blue LED lamp (3 cm away) while the reaction temperature was maintained at 25 °C with cooling water for 14 hours. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: UniSil 10-120C18 50×250 mm; mobile phase: [water (FA)-ACN]; B%: 1%-30%, 22 min) to give the title compound (800 mg, 48% yield) as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.46 (d, J=3.2 Hz, 2H) 7.08 (d, J=4.4 Hz, 2H) 4.63 (s, 1H) 3.11-3.06 (m, 2H) 2.58 (t, J=7.6 Hz, 2H) 1.67-1.59 (m, 2H) 1.51-1.46 (m, 2H) 1.42 (s, 9H) 1.37-1.30 (m, 2H). LC-MS(ESI ⁺ )m/z 264.9(M+H) ⁺ .

Step 2 - tert-Butyl N-[5-(4-piperidinyl)pentyl]carbamate

To a solution of tert _-butyl N-[5-(4-pyridinyl)pentyl]carbamate (800 mg, 3 mmol) in EtOH (8 mL) was added _PtO (687 mg, 3.03 mmol) and AcOH (363 mg, 6.05 mmol) under N. The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred under _H (15 psi) at 25 °C for 12 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (775 mg, 95% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.61 (s, 1H) 3.35 (d, J = 12.4 Hz, 2H) 3.10-2.99 (m, 2H) 2.80 (t, J = 11.2 Hz, 2H) 1.79 (d, J = 11.6 Hz, 2H) 1.41 (s, 15H) 1.26 (s, 6H). LC-MS(ESI ⁺ )m/z 271.2(M+H) ⁺ .

1-[4-[4-(5-aminopentyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate DV)

Step 1 - N-[5-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]benzene tert-Butyl]-4-piperidinyl]pentyl]carbamate

tert-Butyl N-[5-(4-piperidinyl)pentyl]carbamate (34.7 mg, 128 μmol, intermediate DU), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (50.0 mg, 128 μmol, intermediate DS), Cs ₂ CO ₃ (418 mg, 1.28 mmol), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; dichloropalladium (12.5 mg, 12.8 μmol) and A mixture of molecular sieves (2.00 mg, 128 μmol) in dioxane (1 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 ° C under N ₂ atmosphere for 16 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 43%-73%, 10min) to give the title compound (50.0 mg, 67% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ )δ8.05-8.04(m,1H)7.43(d,J＝8.4Hz,2H)7.12(d,J＝8.8Hz,2H)6.93(d,J＝8.8Hz,2H)6.86-6.78(m,2H)4.95(s,2H)3.78(s,3H)3.72(t,J＝6.4Hz,2H)3.6 4(d,J＝12.4Hz,2H)3.16-3.06(m,2H)2.85(t,J＝6.8Hz,2H)2.68(t,J＝11.6Hz,2H)1.77(d,J＝10.4Hz,2H)1.53-1.48(m,2H)1.45(s,9H)1.38-1.24(m,9 H). LC-MS(ESI ⁺ )m/z 579.3(M+H) ⁺ .

Step 2-1-[4-[4-(5-aminopentyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[5-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]pentyl]carbamate (50.0 mg, 86.3 μmol) in TfOH (0.1 mL) was added TFA (924 mg, 8.10 mmol). The mixture was stirred at 70 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (30.0 mg, 97% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 359.1 (M+H) ⁺ .

N-isopropylacetamidine (Intermediate DW)

To a solution of ethyl acetimidate hydrochloride (10.0 g, 80.9 mmol, CAS# 2208-07-3) in IPA (60 mL) was added TEA (8.19 g, 80.9 mmol) and propan-2-amine (4.78 g, 80.9 mmol, CAS# 4432-77-3). The mixture was stirred at 25 °C for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (5.5 g, 67% yield) as a colorless oil.

3-Chloro-4,4-diethoxy-butan-2-one (Intermediate DX)

To a stirred solution of diethoxymethoxyethane (16.0 g, 108 mmol, CAS#122-51-0) in DCM (150 mL) was added diethyl hydrohydroxy (trifluoro) borate (32.6 g, 108 mmol, 47% solution) at -30 °C under _N2 atmosphere. The reaction mixture was stirred at 25 °C for 1 hr. Quick 1-chloropropane-2-one (5.00 g, 54.0 mmol, CAS#78-95-5) was then added at -78 °C, followed by DIPEA (20.9 g, 162 mmol). The reaction mixture was then stirred at -78 °C for 1 hr. Saturated _NaHCO3 (100 mL) was added to the reaction and stirred for 15 min, and the layers were separated. The aqueous phase was extracted with DCM (2 x 100 mL). _{The combined organic layers were washed with H2SO4:H2O ( 1:10} ) ratio followed by water (2 x 100 mL). _The organic layer was dried over anhydrous _Na2SO4 and concentrated under reduced pressure to give the title compound (10.0 g, 47% yield) as a red oil.

[4-(3-Isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl] trifluoromethanesulfonate (Intermediate DY)

Step 1-1-(3-isopropyl-2-methyl-imidazol-4-yl)ethanone

A mixture of 3-chloro-4,4-diethoxy-butan-2-one (10.0 g, 51.3 mmol, intermediate DX), N-isopropylacetamidine (5.15 g, 51.3 mmol, intermediate DW), K ₂ CO ₃ (21.3 g, 154 mmol) and 18-crown-6 (678 mg, 2.57 mmol) in ACN (100 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 80 °C under N ₂ atmosphere for 16 hr. The reaction mixture was partitioned between H ₂ O (100 mL) and EA (2×100 mL). The organic phase was separated, washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM/IPA=100/1 to 10/1) to give the title compound (5.00 g, 58% yield) as a red oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72 (s, 1H), 5.43-5.22 (m, 1H), 2.54 (s, 3H), 2.46 (s, 3H), 1.52 (s, 3H), 1.50 (s, 3H). LCMS (ESI ⁺ ) m/z 167.1 (M+H) ⁺ .

Step 2-(E)-3-(Dimethylamino)-1-(3-isopropyl-2-methyl-imidazol-4-yl)prop-2-en-1-one

To a solution of 1-(3-isopropyl-2-methyl-imidazol-4-yl)ethanone (5.00 g, 30.0 mmol) in DMF (30 mL) was added DMF-DMA (3.94 g, 33.0 mmol, CAS #4637-24-5). The mixture was stirred at 130 °C for 16 hr. The reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by column chromatography (SiO ₂ , DCM/IPA=100/1 to 10/1) to give the title compound (3.00 g, 45% yield) as a red oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.66(d,J＝12.4Hz,1H),7.48(s,1H),5.49(d,J＝12.4Hz,1H),5.47-5.40(m,1H),3.14-2.87(m,6H),2.60(s,3H),1.56(s,3H),1.5 4(s,3H). LCMS(ESI ⁺ )m/z 222.2(M+H) ⁺ .

Step 3-4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-ol

A solution of (E)-3-(dimethylamino)-1-(3-isopropyl-2-methyl-imidazol-4-yl)prop-2-en-1-one (2.00 g, 9.04 mmol), CH ₃ ONa (1.95 g, 36.1 mmol) and urea (1.36 g, 22.5 mmol, CAS# 506-89-8) in 1-butanol (20 mL) was stirred at 140° C. for 16 hr. After completion, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by prep-HPLC (column: Phenomenex C18 250*50mm*10 μm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 0%-20%, 8 min) to give the title compound (1.10 g, 55% yield) as a white solid. LCMS (ESI ⁺ ) m/z 219.0 (M+H) ⁺ .

Step 4-[4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl]trifluoromethanesulfonate

To a solution of 4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-ol (550 mg, 2.52 mmol) in DCM (5 mL) was added TEA (509 mg, 5.04 mmol) and _Tf2O (746 mg, 2.65 mmol). The mixture was stirred at 0 °C for 1 hr. Upon completion, the reaction mixture was partitioned between _H2O (50 mL) and DCM (50 mL). The organic phase was separated, washed with brine (50 _mL ), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue to afford the title compound (780 mg, 88% yield) as a red solid. LCMS (ESI ⁺ ) m/z 350.9 (M+H) ⁺ .

4-[[4-(3-Isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (intermediate DZ)

Step 1 - N-(4-Benzylthio-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidine- 2-Amine

A mixture of [4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl]trifluoromethanesulfonate (780 mg, 2.23 mmol, intermediate DY), 4-benzylsulfanyl-2-methyl-aniline (459 mg, 2.00 mmol, intermediate DE), Pd(OAc) ₂ (49.9 mg, 222 μmol), BINAP (138 _mg , 222 μmol) and _Cs2CO3 (2.18 g, 6.68 mmol) in toluene (10 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100 °C under _N2 atmosphere for 16 hr. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (270 mg, 28% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 430.4 (M+H) ⁺ .

Step 2-4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chlorine

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)pyrimidin-2-amine (30.0 mg, 69.8 μmol) in a mixed solution of ACN (1 mL), AcOH (0.1 mL) and H ₂ O (0.02 mL) was added NCS (23.3 mg, 174 μmol). The mixture was stirred at 25 °C in the dark for 1 hr. The mixture was diluted with water (15 mL) and extracted with EA (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (28.0 mg, 98% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 405.7 (M+H) ⁺ .

N-(4-Benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate EA)

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (500 mg, 2.30 mmol, CAS# 3932-97-6) in a mixed solvent of DCE (6 mL) and t-BuOH (6 mL) was added ZnCl ₂ (1 M, 2.77 mL) at 0° C. After 1 hour, a solution of 4-benzylsulfanyl-2-methyl-aniline (528 mg, 2.30 mmol, intermediate DE) and TEA (256 mg, 2.5 mmol) in a mixed solvent of DCE (3 mL) and t-BuOH (3 mL) was added dropwise to the above solution. The mixture was then stirred at 25° C. for 16 hr. Upon completion, the mixture was diluted with H ₂ O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with saturated NaCl (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=50:1 to 20:1) to give the title compound (600 mg, 63% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 8.66-8.60 (m, 1H), 7.40-7.35 (m, 2H), 7.31-7.28 (m, 2H), 7.28-7.21 (m, 3H), 7.20-7.16 (m, 1H), 4.24 (s, 2H), 2.15 (s, 3H). LC-MS (ESI ⁺ ) m/z 410.0 (M+H) ⁺ .

Isopropylcarbamic acid (1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (intermediate ED)

Step 1-(1-(tert-butyl)-3-((1S,3S)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H- Benzyl pyrazol-5-yl)carbamate

To a mixture of _benzyl (1-(tert-butyl)-3-((1R,3S)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (1.00 g, 2.80 mmol, CAS#2460255-81-4) and 4-nitrophenyl chloroformate (845 mg, 4.20 mmol, CAS#7693-46-1) in DCM (10 mL) at 20 °C under N2 atmosphere was added DMAP (34.1 mg, 279 μmol) and pyridine (663 mg, 8.39 mmol). The mixture was then stirred at 20 °C under nitrogen atmosphere for 10 h. Upon completion, the reaction mixture was poured into ice water (20 mL) and extracted with DCM (30 mL x 2). The combined organic phases were washed with brine (20 mL x 2) and then dried over _Na2SO4 . The mixture was filtered and the _filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (1.4 g, 96% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.28 (d, J=9.2 Hz, 2H), 7.48-7.31 (m, 6H), 6.31-6.05 (m, 2H), 5.30-5.23 (m, 1H), 5.21 (s, 2H), 3.23-3.09 (m, 1H), 2.62 (ddd, J=7.2, 8.0, 14.8 Hz, 1H), 2.18-2.08 (m, 1H), 2.05-1.95 (m, 3H), 1.94-1.87 (m, 1H), 1.59 (s, 10H).

Step T2-(1-(tert-butyl)-3-((1R,3S)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrrolidone Benzyl oxazol-5-yl)carbamate

To a solution of [(1S,3R)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl](4-nitrophenyl)carbonate (600 mg, 1.15 mmol) and propan-2-amine (135 mg, 2.30 mmol) in THF (6 mL) was added DIEA (742 mg, 5.74 mmol). The mixture was stirred at 20 °C for 4 h. After completion, the reaction mixture was poured into ice water (6 mL) and extracted with DCM (6 mL×2). The combined organic phases were washed with brine (6 mL×2) and dried over Na ₂ SO _4. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=10:1 to 3:1) to give the title compound (350 mg, 69% yield) as a colorless oil. LC-MS (ESI+) m/z 443.4 (M+H)+.

Step 3-(1S,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate

To a solution of N-[2-tert-butyl-5-[(1R,3S)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]carbamic acid benzyl ester (350 mg, 790 μmol) in EtOH (20 mL) was added Pd/C (400 mg, 377 μmol, 10 wt%). The mixture was stirred at 20 °C under _H2 atmosphere (15 psi) for 12 h. After completion, the reaction mixture was filtered and the filter cake was washed with EtOH (10 mL). The mixture was filtered and the filtrate was concentrated to give the title compound (260 mg) as a yellow oil. LC-MS (ESI+) m/z 309.2 (M+H)+.

4-((5-amino-1-(3-methylthiophene-2-carbonyl)-1H-1,2,4-triazol-3-yl)amino)-N-(2-(propan-2- (Alkyn-1-yloxy)ethyl)benzenesulfonamide (Intermediate EE)

Step 1 - tert-Butyl N-[4-(tert-Butyloxycarbonylamino)phenyl]sulfonylcarbamate

A solution of 4-aminobenzenesulfonamide (50 g, 290 mmol, 50 mL), (Boc) ₂ O (126 g, 580 mmol, 133 mL), DMAP (3.55 g, 29.0 mmol), and Et ₃ N (88.1 g, 871 mmol, 121 mL) in THF (200 mL) was stirred at 20° C. for 8 h. Upon completion, the reaction mixture was quenched by the addition of H ₂ O (300 mL) at 20° C. and extracted with EtOAc (200 mL×3). The combined organic layers were washed with brine (200 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , dichloromethane:methanol=1/0 to 50/1) to give the title compound (20 g, 19% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ )δ=7.99-7.88(m,2H),7.57-7.46(m,2H),3.50(s,1H),1.53(s,9H),1.41-1.38(m,9H)

Step 2-(4-((tert-butyloxycarbonyl)amino)phenyl)sulfonyl(2-(prop-2-yn-1-yloxy)ethyl)amino Tert-Butyl Formate

To a solution of tert-butyl N-[4-(tert-butoxycarbonylamino)phenyl]sulfonylcarbamate (10 g, 26.8 mmol), 2-prop-2-ynyloxyethanol (3.49 g, 34.9 mmol, CAS# 3973-18-0) and PPh ₃ (9.16 g, 34.91 mmol) in toluene (150 mL) was slowly added dropwise a solution of DIAD (7.06 g, 34.9 mmol, 6.79 mL) in toluene (50 mL) at 0° C. under a stream of nitrogen. The reaction was then stirred at 20° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (200 mL) and extracted with ethyl acetate (150 mL×2). The combined organic phases were washed with brine (100 mL×2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:15) to give the title compound (17 g) as a yellow oil. LC-MS (ESI ⁺ ) m/z 448.1 (MH) ⁻ .

Step 3 -(4-((tert-Butyloxycarbonyl)amino)phenyl)sulfonyl(2-(prop-2-yn-1-yloxy)ethyl)amino Tert-Butyl Formate

To a solution of tert-butyl N-[4-(tert-butoxycarbonylamino)phenyl]sulfonyl-N-(2-prop-2-ynyloxyethyl)carbamate (17 g, 37.4 mmol) in DCM (300 mL) was added TFA (52.3 g, 459 mmol) at 20 ° C under a nitrogen stream. The reactants were then stirred at 20 ° C under a nitrogen atmosphere for 10 h. After completion, the reactants were concentrated to give a residue. The crude product was purified by reverse phase HPLC (0.1% NH3·H2O conditions) to give the title compound (7 g, 74% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.63 (d, J = 8.8Hz, 2H), 6.68 (d, J = 8.6Hz, 2H), 6.40 (br s, 3H), 4.11-3.99 (m, 2H), 3.56 (t, J = 5.2Hz, 2H), 3.19-3.09 (m, 2H), 2.43 (t ,J=2.4Hz,1H).

Step 4-N-(2-(prop-2-yn-1-yloxy)ethyl)-4-thiocyanatobenzenesulfonamide

To a solution of thiocarbonyl dichloride (3.16 g, 27.5 mmol) in DCM (70 mL) was slowly added dropwise a solution of 4-amino-N-(2-prop-2-ynyloxyethyl)benzenesulfonamide (7 g, 27.53 mmol) in DCM (70 mL) at 0 ° C. The reactants were then stirred at 20 ° C under a nitrogen atmosphere for 10 h. After completion, the reactants were poured into water (150 mL) and extracted with dichloromethane (100 mL × 2). The combined organic phases were washed with brine (3 mL × 2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give the title compound (7 g, 86% yield) as a brown solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.86 (br d, J = 7.8Hz, 2H), 7.32 (br d, J = 8.4Hz, 2H), 5.31-5.16 (m, 1H), 4.08 (s, 2H), 3.56 (br t, J = 4.8Hz, 2H), 3.18 (br d, J = 4.8Hz, 2H ),2.49-2.41(m,1H).

Step 5-3,5-dimethyl-N-((4-(N-(2-(prop-2-yn-1-yloxy)ethyl)sulfamoyl)phenyl)sulfide ((2-( ...-1H-pyrazole-1-1H-pyrazole-1-carboxamidine

To a solution of 3,5-dimethylpyrazole-1-carboximidamide; nitric acid (9.50 g, 47.2 mmol, CAS# 22906-75-8) in DMF (140 mL) was added KOH (2.65 g, 47.24 mmol) at 0 ° C under a stream of nitrogen. To this was slowly added dropwise a solution of 3,5-dimethyl-1H-pyrazole-1-carboximidamide (7 g, 23.62 mmol) in DMF (70 mL) at 0 ° C. The reactants were then stirred at 60 ° C under a nitrogen atmosphere for 10 h. After completion, the reactants were poured into a saturated aqueous ammonium chloride solution (300 mL) and extracted with ethyl acetate (200 mL×2). The combined organic phases were washed with brine (200 mL×2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:7) to give the title compound (2.7 g, 26% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=8.02 (s, 4H), 7.82 (d, J=8.4 Hz, 2H), 5.96 (d, J=10.0 Hz, 2H), 4.09 (d, J=2.4 Hz, 2H), 3.57 (t, J=5.2 Hz, 2H), 3.17 (t, J=5.2 Hz, 2H), 2.44 (t, J=2.4 Hz, 1H), 2.23 (d, J=6.4 Hz, 6H)

Step 6-4-((5-amino-1H-1,2,4-triazol-3-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl Benzenesulfonamide

To a solution of 3,5-dimethyl-N-((4-(N-(2-(prop-2-yn-1-yloxy)ethyl)sulfamoyl)phenyl)carbamothioyl)-1H-pyrazole-1-carboximidamide (1 g, 2.30 mmol) in THF (20 mL) was added hydrazine; hydrate (1.29 g, 25.7 mmol) at 20 °C under a stream of nitrogen. The reactants were then stirred at 55 °C under a nitrogen atmosphere for 3 h. Upon completion, the reactants were concentrated to give a residue. The solid was refluxed in a solvent of EtOAc:PE=1:3 (50 mL) for 5 min. The mixture was then filtered and the filter cake was washed with EtOAc:PE=1:3 (30 mL) and dried in vacuo to give the title compound (320 mg, 41.34% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.29 (br s, 1H), 9.15-8.84 (m, 1H), 7.71-7.47 (m, 4H), 5.98 (s, 2H), 5.60 (br s, 1H), 4.07 (d, J = 2.4Hz, 2H), 3.43-3.38 (m, 2H), 2.90-2.79(m,2H),1.74(s,1H).

Step 7-4-((5-amino-1-(3-methylthiophene-2-carbonyl)-1H-1,2,4-triazol-3-yl)amino)-N-(2- (Prop-2-yn-1-yloxy)ethyl)benzenesulfonamide

To a solution of 4-((5-amino-1H-1,2,4-triazol-3-yl)amino)-N-(2-(prop-2-yn-1-yloxy)ethyl)benzenesulfonamide (280 mg, 832 μmol) in pyridine (3 mL) and THF (3 mL) was added 3-methylthiophene-2-carbonyl chloride (267 mg, 1.66 mmol, CAS# 61341-26-2) at 0°C under a stream of nitrogen. The reaction was then stirred at 20°C under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with brine (2 x 20 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min) to give the title compound (120 mg, 31% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 9.92 (s, 1H), 8.05 (d, J = 5.2Hz, 1H), 7.91-7.78 (m, 4H), 7.77-7.70 (m, 2H), 7.48 (t, J = 6.4Hz, 1H), 7.16 (d, J = 5.2Hz, 1H), 4.08 (d,J＝2.4Hz,2H),3.44-3.40(m,2H),2.89(q,J＝6.0Hz,2H),2.63(s,3H),2.57-2.55(m,1H).

4-[(8-Cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (intermediate EF)

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-8-cyclopentyl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.26 mmol, synthesized via step 1-2 of Intermediate CW) in ACN (10 mL), AcOH (1 mL), H ₂ O (0.5 mL) was added NCS (754 mg, 5.65 mmol) in the dark. The mixture was stirred at 25° C. in the dark for 0.5 hr. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (2×60 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA=0:1, P1, Rf=0.45) to give the title compound (900 mg, 95% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.81 (s, 1H), 8.82 (s, 1H), 7.85 (d, J = 9.6Hz, 1H), 7.60 (s, 1H), 7.54-7.51 (m, 1H), 7.47-7.44 (m, 1H), 7.41-7.35 (m, 1H), 7.3 2-7.29(m,1H),6.43(d,J＝9.6Hz,1H),5.77-5.63(m,1H),2.31(s,3H),2.16(d,J＝4.8Hz,2H),1.72(s,3H),1.49(s,1H). LC-MS(ESI ⁺ )m/z 419.0(M+H) ⁺ .

3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate EG)

Step 1-3-[4-[tert-Butyloxycarbonyl(methyl)amino]-1-piperidinyl]-2-nitro-benzoic acid methyl ester

To a solution of 3-fluoro-2-nitro-benzoic acid methyl ester (10.0 g, 50.2 mmol, CAS#1214353-57-7), tert-butyl N-methyl-N-(4-piperidinyl)carbamate (13.9 g, 65.2 mmol, CAS#108612-54-0) in ACN (250 mL) was added DIEA (19.4 g, 150 mmol). The mixture was stirred at 50 °C for 16 hr. Upon completion, the mixture was concentrated in vacuo. The mixture was triturated with _H2O (200 mL), filtered and the filtrate was dried in vacuo to give the title compound (19.6 g, 99% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.85 (dd, J = 1.2, 8.0Hz, 1H), 7.79-7.75 (m, 1H), 7.73-7.66 (m, 1H), 3.84 (s, 3H), 4.04-3.68 (m, 1H), 3.11-3.01 (m, 2H), 2.95-2 .82(m,2H),2.70(s,3H),1.79-1.55(m,4H),1.41(s,9H), LC-MS(ESI ⁺ )m/z 416.1(M+Na) ⁺ .

Step 2-Methyl 2-amino-3-[4-[tert-butyloxycarbonyl(methyl)amino]-1-piperidinyl]benzoate

To a solution of 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]-2-nitro-benzoic acid methyl ester (18.6 g, 47.2 mmol) in THF (190 mL) was added Pd/C (2.00 g, 10% wt). The mixture was stirred at 25 °C under _H2 (15 Psi) for 16 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (17.1 g, 99% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.61-7.51(m,1H),7.10-7.01(m,1H),6.52(t,J＝8.0Hz,1H),6.25-6.04(m,2H),4.20-3.88(m,1H),3.79(s,3H),3.15-2.99(m, 2H),2.74(s,3H),2.68-2.51(m,2H),1.87-1.66(m,4H),1.41(s,9H).

Step 3-3-[4-[tert-Butyloxycarbonyl(methyl)amino]-1-piperidinyl]-2-(methylamino)benzoic acid methyl ester

To a solution of methyl 2-amino-3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]benzoate (12.1 g, 33.3 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (45.0 mL) was added methyl trifluoromethanesulfonate (8.21 g, 50.0 mmol). The mixture was stirred at 25° C. for 1 hr. Upon completion, the mixture was diluted with H ₂ O (300 mL) and extracted with EA (3×100 mL). The organic layer was washed with brine (3 x 100 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound as a yellow oil (12.5 g, 99% yield), ^1H NMR (400 MHz, _CDCl3 ) δ 7.59 (dd, J = 1.2, 8.0 Hz, 1H), 7.20-7.12 (m, 1H), 6.72 (t, J = 8.0 Hz, 1H), 4.23-3.95 (m, 1H), 3.89 (s, 3H), 3.35-3.23 (m, 2H), 3.01 (s, 3H), 2.82 (s, 3H), 2.70-2.59 (m, 2H), 1.93-1.85 (m, 2H), 1.78-1.71 (m, 2H), 1.50 (s, 9H).

Step 4-3-[4-[tert-Butyloxycarbonyl(methyl)amino]-1-piperidinyl]-2-(methylamino)benzoic acid

To a solution of methyl 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]-2-(methylamino)benzoate (12.5 g, 33.1 mmol) in MeOH (120 mL) and H ₂ O (20 mL) was added LiOH.H ₂ O (4.17 g, 99.3 mmol). The mixture was stirred at 60 °C for 12 hr. After completion, the mixture was concentrated in vacuo. The mixture was diluted with H ₂ O (150 mL) and extracted with EA (3×50 mL). The aqueous phase was acidified with 1 N HCl solution until pH=5. The mixture was then extracted with EA (3×80 mL), the organic layer was washed with brine (3×80 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (11.0 g, 91% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.99-7.87(m,1H),7.41-7.35(m,1H),7.19-7.08(m,1H),4.16-3.81(m,1H),3.15-3.08(m,2H),2.95-2.88(m,3H),2.88-2.7 9(m,5H),2.00-1.85(m,2H),1.83-1.74(m,2H),1.50(s,9H).

Step 5 - N-methyl-N-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]carbamic acid Tert-butyl ester

To a solution of 3-[4-[tert-butoxycarbonyl(methyl)amino]-1-piperidinyl]-2-(methylamino)benzoic acid (12.5 g, 34.3 mmol) and DIEA (13.3 g, 103 mmol) in t-BuOH (130 mL) was added DPPA (11.3 g, 41.2 mmol) at 0°C. The mixture was stirred at 90°C for 16 hr. After completion, the mixture was concentrated in vacuo. The mixture was diluted with _H2O (200 mL) and extracted with EA (3 x ₈₀ mL). The organic layer was washed with brine (3 x 50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The mixture was purified by reverse phase: (0.1% _NH3.H2O ) to give the title compound (5.4 g, 43% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.80(s,1H),6.95-6.87(m,1H),6.87-6.80(m,1H),6.76-6.70(m,1H),4.01-3.71(m,1H),3.58(s,3H),3.20-3.06(m,2H), 2.81-2.69(m,5H),1.96-1.79(m,2H),1.72-1.56(m,2H),1.42(s,9H), LC-MS(ESI ⁺ )m/z 361.2(M+H) ⁺ .

Step 6 - N-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2- [Oxo-benzoimidazol-4-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester

To a solution of tert-butyl N-methyl-N-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]carbamate (5.40 g, 14.9 mmol) in THF (60 mL) was added t-BuOK (3.03 g, 26.9 mmol) at -10°C. The mixture was stirred at -10°C for 0.5 hr. A solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (10.2 g, 26.9 mmol, Intermediate G) in THF (50 mL) was then added to the above mixture. The mixture was stirred at 25°C for 16 hr. Upon completion, the mixture was quenched with saturated NH ₄ Cl solution (80 mL) and concentrated in vacuo to remove THF. The mixture was then extracted with EA (3×50 mL), the organic layer was washed with brine (2×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (6.2 g, 69% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.25-7.18(m,2H),6.97-6.90(m,2H),6.90-6.80(m,3H),5.57-5.45(m,1H),4.89-4.74(m,2H),4.07-3.80(m,1H),3.73(s,3H),3.65(s,3H),3. 20-3.12(m,2H),3.10-2.98(m,1H),2.88-2.77(m,3H),2.75(s,3H),2.74-2.68(m,1H),2.09-2.00(m,1H),1.98-1.84(m,2H),1.71-1.60(m,2H), 1.43(s,9H),LC-MS(ESI ⁺ )m/z 592.4(M+H) ⁺ .

Step 7-3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidin-2, 6-Dione

A solution of N-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester (2.70 g, 4.56 mmol) in TFA (30 mL) and TfOH (3.8 mL) was stirred at 60 ° C for 16 hr. After completion, the mixture was concentrated in vacuo. The residue was then adjusted to pH = 3 with saturated NaHCO ₃ solution. The mixture was purified by reverse phase (0.1% FA) to give the title compound (1.6 g, 94% yield) as a blue solid. ² _.95-2.85 (m,1H),2.82-2.69(m,3H),2.68-2.63(m,1H),2.61(s,3H),2.14-2.05(m,2H),2.04-1.95(m,1H),1.83-1.66(m,2H).

Step 8 - N-[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl [piperidinyl]-N-methyl-carbamic acid tert-butyl ester

To a solution of 3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (1.5 g, 4.04 mmol), TEA (817 mg, 8.08 mmol) in ACN (15.0 mL) was added (Boc) ₂ O (1.32 g, 6.06 mmol). The mixture was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=1:1) to give the title compound (700 mg, 36% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.08(s,1H),7.01-6.91(m,2H),6.90-6.83(m,1H),5.45-5.27(m,1H),3.97-3.76(m,1H),3.64(s,3H),3.20-3.10(m,2H),2.95-2.83(m,1H),2 .82-2.76(m,2H),2.74(s,3H),2.73-2.64(m,1H),2.64-2.56(m,1H),2.04-1.98(m,1H),1.95-1.83(m,2H),1.70-1.58(m,2H),1.41(s,9H),LC-MS( ESI ⁺ )m/z 472.3(M+H) ⁺ .

Step 9-3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidin-2, 6-Dione

To a solution of tert-butyl N-[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]-N-methylcarbamate (500 mg, 1.06 mmol) in DCM (10.0 mL) was added HCl/dioxane (4.00 M, 6.00 mL). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (430 mg, 99% yield, HCl) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10(s,1H),8.96(s,1H),7.04-6.97(m,1H),6.97-6.89(m,2H),5.44-5.30(m,1H),3.64(s,3H),3.26-3.14(m,2H),3.14-3 .02(m,1H),2.98-2.84(m,1H),2.81-2.72(m,2H),2.70-2.60(m,2H),2.60 -2.56(m,3H),2.19-2.08(m,2H),2.05-1.95(m,1H),1.87-1.69(m,2H),LC -MS(ESI ⁺ )m/z 372.2(M+H) ⁺

3-[3-methyl-4-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]-2-oxo-benzimidazole-1- [4-(2-[ ...piperidin-2,6-dione)]]piperidin-2,6-dione (Intermediate EH)

Step 1-4-[[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4- [piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of 3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (1.43 g, 3.51 mmol, HCl, intermediate EG) and tert-butyl 4-formylpiperidine-1-carboxylate (822 mg, 3.86 mmol, CAS# 137076-22-3) in a mixed solvent of THF (40 mL) and DMF (20 mL) were added KOAc (3.44 g, 35.0 mmol) and NaBH(OAc) ₃ (1.49 g, 7.01 mmol). The mixture was stirred at 25° C. for 2 hr. Upon completion, the mixture was quenched with H ₂ O (1 mL), diluted with H ₂ O (30 mL), and extracted with EA (3×50 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the organic liquid was concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50 mm*7 μm; mobile phase: [water (HCl)-ACN]; B%: 10%-40%, 20 min) to give the title compound (1.00 g, 50% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ )δ10.51(s,1H),8.92-8.82(m,1H),6.94-6.88(m,2H),5.37(dd,J＝5.2,12.8Hz,1H),3.64(s,3H),3.41-3.32(m,2H),3.26-3.22(m,2H),2.98-2.88(m ,4H),2.76(d,J ＝4.8Hz,3H),2.68-2.66(m,1H),2.25-2.09(m,4H),2.08-1.97(m,3H),1.96-1.90(m,2H),1.83-1.73(m,2H),1.67-1.61(m,2H),1.51-1.43(m,2H), 1.42-1.36(m,9H). LC-MS(ESI ⁺ )m/z 569.3(M+H) ⁺ .

Step 2-3-[3-methyl-4-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]-2-oxo-benzimidazole oxazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylate (100 mg, 175 μmol) in DCM (2 mL) was added HCl/dioxane (4 M, 1.00 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (88 mg, 99% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 469.1 (M+H) ⁺ .

2-(Prop-2-yn-1-yloxy)ethyl 4-methylbenzenesulfonate (Intermediate EI)

To a solution of 2-prop-2-ynyloxyethanol (5 g, 49.9 mmol, CAS#3973-18-0), 4-methylbenzenesulfonyl chloride (11.4 g, 59.9 mmol) in DCM (60 mL) was added TEA (15.1 g, 149 mmol) at 0°C. The mixture was stirred at 25°C for 12 h. Upon completion, the mixture was quenched with sat.aq. NH ₄ Cl (60 mL) and extracted with EtOAc (60 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=8/1 to 3/1) to give the title compound (8.2 g, 58.11% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d6) δ = 7.82-7.80 (m, 2H), 7.36-7.34 (m, 2H), 4.21-4.18 (t, 2H), 4.12 (s, 2H), 3.74-3.72 (m, 2H), 2.45 (s, 3H), 2.43 (s, 1H).

Isopropylcarbamic acid (1R, 3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(2-(prop-2-yn-1-yloxy) (ethyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate EJ)

A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-(2-piperazin-1-ylethyl)pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (0.15 g, 291 μmol, synthesized via step 1-2 of Intermediate BH), 2-prop-2-ynyloxyethyl 4-methylbenzenesulfonate (66.7 mg, 262 μmol, Intermediate EI), Cs ₂ CO ₃ (759 mg, 2.33 mmol), and KI (9.68 mg, 58.2 μmol) in DMF (6 mL) was stirred at 70° C. for 12 h. After completion, the mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic phase was washed with brine (10 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=0:1) to give the title compound (0.07 g, 36% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 597.4 (M+H) ⁺ .

3-[5-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate EK)

Step 1 - tert-Butyl N-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (3.00 g, 12.0 mmol), 3-bromoprop-1-yne (1.72 g, 14.4 mmol, 1.24 mL), TBAI (356 mg, 962 μmol), KI (299 mg, 1.81 mmol) and KOH (675 mg, 12.0 mmol) in THF (30 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 25 ° C under N ₂ atmosphere for 16 hr. After completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (2.50 g, 72% yield) as a light yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ5.05 (s, 1H), 4.22 (d, J = 2.4Hz, 2H), 3.76-3.60 (m, 8H), 3.55 (t, J = 5.2Hz, 2H), 3.35-3.27 (m, 2H), 2.44 (t, J = 2.4Hz, 1H), 1.47 (s, 9H ).

Step 2-N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole- tert-Butyl 5-yl]prop-2-ynyloxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl]carbamate (849 mg, 2.96 mmol), 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, Intermediate J), Pd(PPh ₃ ) ₂ Cl ₂ (311 mg, 443 μmol), CuI (84 mg, 443 μmol) and TEA (2.69 g, 26.6 mmol, 3.70 mL) in DMF (15 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 80 °C under N ₂ atmosphere for 3 hr. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA) to give the title compound (400 mg, 49% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12 (s, 1H), 7.33 (s, 1H), 7.21-7.12 (m, 2H), 6.77-6.71 (m, 1H), 5.39 (dd, J = 5.2, 12.8Hz, 1H), 4.40 (s, 2H), 3.68-3.62 (m, 2H) ,3.61-3.56(m,2H),3.55-3.47(m,6H),3.35(s,3H),3.07(q,J＝6.0Hz,2H),2.96-2.80(m,1H),2.72-2.58(m,2H),2.08-1.99(m,1H),1.37(s,9H).

Step 3 - N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole- tert-Butyl 5-[propyloxy]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]prop-2-ynyloxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 734 μmol) in THF (100 mL) was added Pd/C (300 mg, 10 wt%) and Pd(OH) ₂ /C (300 mg, 10 wt%). The mixture was stirred at 20 °C under _H2 (15 psi) atmosphere for 4 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (270 mg, 67% yield) as a light yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.07 (s, 1H), 7.08-6.96 (m, 2H), 6.87 (d, J = 7.2Hz, 1H), 6.73 (s, 1H), 5.34 (dd, J = 5.2, 12.4Hz, 1H), 3.69-3.35 (m, 15H), 3.09- 3.01(m,2H),2.97-2.81(m,1H),2.77-2.57(m,4H),2.08-1.94(m,1H),1.89-1.71(m,2H),1.37(s,9H).

Step 4-3-[5-[3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propyl]-3-methyl-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]propoxy]ethoxy]ethoxy]ethyl]carbamate (270 mg, 492 μmol) in DCM (10 mL) was added HCl/dioxane (4 M, 5 mL). The mixture was then stirred at 25 °C for 3 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (220 mg, 92% yield) as a pale yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08 (s, 1H), 7.86 (s, 3H), 7.07-6.97 (m, 2H), 6.91-6.84 (m, 1H), 5.40-5.29 (m, 1H), 3.61 (t, J = 5.2Hz, 2H), 3.59-3.56 (m, 4H) ,3.55-3.53(m,2H),3.52-3.48(m,2H),3.43-3.40(m,2H),3.33(s,3H),3.02-2.84(m,3H),2.76-2.58(m,4H),2.05-1.97(m,1H),1.87-1.73(m,2H) .

Isopropylcarbamic acid (1R, 3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(4-(prop-2-yn-1-yloxy) (butyl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate EL)

A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-(2-piperazin-1-ylethyl)pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (0.5 g, 971 μmol, synthesized via step 1-2 of intermediate BH), 4-prop-2-ynyloxybutyl 4-methylbenzenesulfonate (246 mg, 874 μmol, CAS# 1125737-76-9), Cs ₂ CO ₃ (1.58 g, 4.86 mmol), and KI (32.2 mg, 194 μmol) in DMF (10 mL) was stirred at 70° C. for 4 h. After completion, the mixture was quenched with sat. NH ₄ Cl (10 mL) and extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (40 mL x 3), dried _{over Na2SO4} , and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 1/1 to 1/2) to give the title compound (180 mg, 27% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 615.8 (M+H) ⁺ .

Benzyl (2-(2-(prop-2-yn-1-yloxy)ethoxy)ethyl)carbamate (Intermediate EM)

To a solution of 2-(2-prop-2-ynyloxyethoxy)ethylamine (0.5 g, 3.49 mmol, CAS# 944561-44-8) in DCM (8 mL) was added TEA (389 mg, 3.84 mmol) and benzyl chloroformate (655 mg, 3.84 mmol). The mixture was stirred at 25 °C for 12 hr. Upon completion, the reaction mixture was poured into water (10 ml), and the solution was subsequently extracted with DCM (10 ml x 3). The organic layer was washed with brine (10 ml x 3), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 2/1) to give the title compound (850 mg, 82% yield) as a white oil. LC-MS (ESI ⁺ ) m/z 278.0 (M+H) ⁺ .

3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d]Imidazol-1-yl)piperidine-2,6-dione (Intermediate EN)

Step 1-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene (d)imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)carbamic acid benzyl ester

To a solution of benzyl N-[2-(2-prop-2-ynyloxyethoxy)ethyl]carbamate (850 mg, 3.07 mmol, intermediate EM) in THF (7 mL) and ACN (7 mL) were added XPhos Pd G3 (778 mg, 920 μmol), Cs ₂ CO ₃ (5.99 g, 18.4 mmol) and 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (1.55 g, 4.60 mmol, intermediate J). The mixture was stirred at 60 °C under N ₂ atmosphere for 12 hr. After completion, the reaction mixture was diluted with water and extracted with DCM (10 mL×3). The organic layer was washed with brine (10 mL×3), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 6/1 to 2/1) to give the title compound (1.2 g, 50% yield) as a yellow solid. LC-MS (ESI+) m/z 535.3 (M+H) ⁺ .

Step 2-3-(5-(3-(2-(2-aminoethoxy)ethoxy)propyl)-3-methyl-2-oxo-2,3-dihydro- 1H-Benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of N-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyloxy]ethoxy]ethyl]carbamic acid benzyl ester (1.2 g, 2.24 mmol) in THF (30 mL) was added Pd/C (2.38 g, 10 wt%). The mixture was stirred at 25 °C under H ₂ (15 PSI) atmosphere for 4 hr. Upon completion, the reaction mixture was filtered and the solution was then concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give the title compound (90 mg, 10% yield) as a white solid. LC-MS (ESI+) m/z 405.2 (M+H) ⁺ .

2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (Intermediate EO)

To a solution of 2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethanol (5 g, 21.5 mmol, CAS#87450-10-0) in DCM (50 mL) was added TEA (6.53 g, 64.6 mmol) and TosCl (4.51 g, 23.7 mmol). The mixture was stirred at 25 °C for 12 hr. After completion, the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (30 mL x 3). The organic layer was dried _{over Na2SO4} and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 4/1 to 1/1) to give the title compound (6.8 g, 60% yield) as a white oil. LC-MS (ESI+) m/z 386.9 (M+H) ⁺ .

2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid (intermediate EP)

Step 1-2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid Methyl ester

To a solution of 2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate (6.8 g, 17.6 mmol, intermediate EO) in DMF (50 mL) were added KI (292 mg, 1.76 mmol) and Cs ₂ CO ₃ (11.5 g, 35.2 mmol) and 1H-pyrazole-5-carboxylic acid methyl ester (2.66 g, 21.1 mmol). The mixture was stirred at 70° C. for 2 hr. After completion, the reaction mixture was diluted with water and extracted with EtOAc (60 mL×3). The organic layer was washed with brine (50 mL×3), dried over Na ₂ SO ₄ , and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=6/1 to 1/1) to give the title compound (3.7 g, 45% yield) as a white oil. LC-MS(ESI+)m/z 341.5(M+H) ⁺ .

Step 2-2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid

To a solution of methyl 2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylate (3.7 g, 10.9 mmol) in MeOH (4 mL), THF (4 mL) and H ₂ O (4 mL) was added LiOH.H ₂ O (1.82 g, 43.5 mmol). The mixture was stirred at 25° C. for 1 hour. After completion, the pH of the mixture was adjusted to 5 with 1 M HCl, followed by extraction with EtOAc (10 mL×3). The organic layer was washed with brine (20 mL×3) and concentrated under reduced pressure to give the title compound (2.6 g) as a white oil. LC-MS (ESI+) m/z 327.2 (M+H) ⁺ .

[(1S,3R)-3-[1-tert-butyl-5-[[2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy [4-(2-yl)-1-(2 ...

To a solution of 2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]ethyl]pyrazole-3-carboxylic acid (0.6 g, 2 mmol, intermediate EP) in ACN (6 mL) was added T ₃ P (3.16 g, 4.96 mmol, 50% solution) and DIEA (1.07 g, 8.27 mmol, 1.44 mL) and [(1S,3R)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (510 mg, 1.65 mmol, intermediate CB). The mixture was stirred at 60° C. for 12 hr. After completion, the reaction mixture was diluted with water (5 mL) and extracted with EtOAc (6 mL×3). The organic layer was washed with brine (6 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=6/1 to 1/2) to give the title compound (240 mg, 23% yield) as a yellow oil. LC-MS (ESI+) m/z 617.4 (M+H) ⁺ .

((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidine-1- tert-Butyl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (CAS#2095244-42-9) (Chinese Intermediate ER)

1-(11-(Benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid (Intermediate ES)

Step 1-11-(Benzyloxy)undec-1-ol

To a suspension of NaH (1.17 g, 29.2 mmol, 60% dispersion in mineral oil) in DMF (30 mL) was slowly added a solution of undecane-1,11-diol (5 g, 26.5 mmol, CAS# 765-04-8) in DMF (20 mL) at -10 °C under nitrogen. The reaction mixture was warmed to 25 °C and stirred for 1 h. Subsequently, the reaction mixture was cooled to 0 °C before BnBr (4.09 g, 23.9 mmol, 2.84 mL) was added dropwise. The reaction mixture was warmed to 25 °C and stirred for another 16 h. Upon completion, it was quenched with saturated aqueous NH ₄ Cl solution (20 mL) at 0 °C, the resulting mixture was extracted with EtOAc (30×3 mL), washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE:EtOAc=5:1) to give the title compound (3.7 g, 50% yield) as a white gum. ¹ H NMR (400 MHz, DMSO-d6) δ=7.45-7.17 (m, 5H), 4.44 (s, 2H), 4.32 (t, J=5.2 Hz, 1H), 3.45-3.34 (m, 4H), 1.56-1.48 (m, 2H), 1.40 (br t, J=6.4 Hz, 2H), 1.24 (s, 14H).

Step 2-4-Methylbenzenesulfonic acid 11-(benzyloxy) undecyl ester

To a solution of 11-(benzyloxy)undecan-1-ol (3.7 g, 10.1 mmol) and TEA (1.43 g, 14.1 mmol, 1.97 mL) in DCM (19 mL) and DMF (19 mL) at 0°C under _N2 was added TosCl (2.89 g, 15.2 mmol), then the mixture was stirred at 25°C for 12 h. Upon completion, the reaction mixture was quenched with saturated aqueous _NaHCO3 solution (30 mL) at 0°C and extracted with DCM (10 x 3 mL). The combined organic layers were washed with brine (10 x 3 mL), dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 25/1 to 5/1) to give the title compound (1.3 g, 30% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO-d6) δ＝12.47-12.04 (m, 1H), 8.28-8.18 (m, 1H), 7.77 (s, 1H), 7.43-7.12 (m, 5H), 4.43 (s, 2H), 4.24-4.07 (m, 3H), 3.40 (t, J＝6.4 Hz, 2H), 1.75 (quintet, J＝7.2 Hz, 2H), 1.51 (quintet, J＝6.8 Hz, 2H), 1.22 (br s, 12H).

Step 3-1-(11-(Benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid methyl ester

To a solution of 1H-pyrazole-4-carboxylic acid methyl ester (395 mg, 3.14 mmol) and 4-methylbenzenesulfonic acid 11-(benzyloxy)undecyl ester (1.3 g, 2.61 mmol) in DMF (7.8 mL) was added Cs ₂ CO ₃ (1.70 g, 5.23 mmol) and KI (43.4 mg, 261 μmol) at 0° C. under a nitrogen stream. The reaction was then stirred at 70° C. under a nitrogen atmosphere for 16 h. Upon completion, the reaction mixture was treated with H ₂ O (20 mL) and extracted with EtOAc (40×3 mL). The organic layer was washed with brine (25×3 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 10/1) to give the title compound (1.3 g) as a yellow oil. LC-MS(ESI ⁺ )m/z 387.7(M+H) ⁺ .

Step 4-1-(11-(Benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid

To a solution of methyl 1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxylate (1.3 g, 3.36 mmol) in THF (18 mL), H ₂ O (3 mL) and MeOH (3 mL) was added LiOH (161 mg, 6.73 mmol), then the mixture was stirred at 40 °C for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) and extracted with EtOAc (10×3 mL). The aqueous phase pH was adjusted to 3-4 by the addition of 2M HCl, then the mixture was extracted with EtOAc (10×3 mL). The combined organic layers were washed with brine (10×3 mL), dried over Na ₂ SO ₄ and evaporated to give the title compound as a white solid (0.7 g). LC-MS (ESI ⁺ ) m/z 373.4 (M+H) ⁺ .

11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrrolidone 1H-pyrazol-1-yl)undecane-4-methylbenzenesulfonate (Intermediate ET)

Step 1-isopropylcarbamic acid (1R, 3S)-3-(5-(1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-yl) (formylamino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester

To a solution of 1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxylic acid (650 mg, 1.74 mmol, Intermediate ES) and (1R,3S)-3-(5-amino-1-isopropyl-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (357 mg, 1.16 mmol, Intermediate U) in ACN (13 mL) was added DIEA (749 mg, 5.80 mmol) and T ₃ P (1.48 g, 2.32 mmol, 50% solution), then the mixture was stirred at 80 °C for 16 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) and extracted with EtOAc (10×3 mL). The combined organic layers were washed with brine (10×3 mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by re-MPLC (water (0.225% FA)-ACN) to give the title compound (160 mg, 20% yield) as a yellow liquid. LC-MS (ESI ⁺ ) m/z 663.5 (M+H) ⁺ .

Step 2-isopropylcarbamic acid (1R, 3S)-3-(1-(tert-butyl)-5-(1-(11-hydroxyundecyl)-1H-pyrrolidone (4-oxadiazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester

To a solution of (1R,3S)-3-(5-(1-(11-(benzyloxy)undecyl)-1H-pyrazole-4-carboxamido)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (130 mg, ₁₉₆ μmol) in EtOH (2 mL) was added Pd/C (13 mg, 35.3 μmol, 10 wt%) under H 2 (15 PSI). The mixture was then stirred at 25° C. for 17 h. After completion, filtration and concentration gave the title compound as a white solid (75 mg). LC-MS (ESI ⁺ ) m/z 573.9 (M+H) ⁺ .

Step 3-4-Methylbenzenesulfonic acid 11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy) (cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl

To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(11-hydroxyundecyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 87.3 μmol) in DCM (1 mL) was added TEA (26.5 mg, 261 μmol). Then 4-methylbenzenesulfonyl chloride (19.9 mg, 104 μmol) was added and the mixture was stirred at 20°C for 12 h. Upon completion, the reaction mixture was quenched with NaHCO ₃ (aq, 20 mL) at 20°C and then diluted with EtOAc (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (120 mg) as a yellow solid. LC-MS(ESI ⁺ )m/z 727.5(M+H) ⁺ .

2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid (intermediate EU

Step 1-2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid ester

To a solution of 2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (3.7 g, 11 mmol, synthesized via step 1 of intermediate BE) and 2-(2-hydroxyphenyl)acetate (1.98 g, 11.8 mmol) in DMF (50 mL) was added Cs ₂ CO ₃ (17.6 g, 54.0 mmol) and KI (179.3 mg, 1.08 mmol) at 0° C. under a stream of nitrogen. The reaction was then stirred at 60° C. under nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into water (70 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were washed with brine (50 mL×2), dried over sodium sulfate, filtered to give the filtrate and concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:25) to give the title compound (2.2 g, 60.5% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 359.1 (M+Na) ⁺ .

Step 2-2-(2-(2-(2-(2-(prop-2-yn-1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetic acid

To a solution of methyl 2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]phenyl]acetate (2.2 g, 6.54 mmol) in THF (22 mL), methanol (11 mL) and H ₂ O (11 mL) was added LiOH.H ₂ O (1.10 g, 26.1 mmol) at 20° C. under a stream of nitrogen. The reaction was then stirred at 20° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into ice water (50 mL) and acidified to pH=4 by 2N hydrochloric acid. The mixture was then extracted with ethyl acetate (70 mL×2). The combined organic phases were washed with brine (50 mL×2), dried over sodium sulfate, then filtered to give a filtrate and concentrated to give the title compound as a colorless oil (1.5 g). LC-MS (ESI ⁺ ) m/z 345.1 (M+Na) ⁺ .

(1S,3R)-3-(1-(tert-butyl)-5-(2-(2-(2-(2-(2-(prop-2-yn-1- yloxy )ethoxy)ethoxy)ethoxy)phenyl)acetamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate EV)

Step 1-isopropylcarbamic acid (1S, 3R)-3-(1-(tert-butyl)-5-(2-(2-(2-(2-(2-prop-2-yne- 1-yloxy)ethoxy)ethoxy)ethoxy)phenyl)acetylamino)-1H-pyrazol-3-yl)cyclopentyl ester

To a solution of 2-[2-[2-[2-(2-prop-2-ynyloxyethoxy)ethoxy]ethoxy]phenyl]acetic acid (0.5 g, 1.55 mmol, intermediate EU) and [(1S,3R)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (478 mg, 1.55 mmol, intermediate CB) in ACN (10 mL) was added T3P (2.96 g, 4.65 mmol, 50% solution) and DIEA (1.00 g, 7.76 mmol) at 0°C under a stream of nitrogen. The reaction was then stirred at 20°C under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into water (15 mL) and extracted with ethyl acetate (20 mL×2). The combined organic phases were washed with brine (20 mL×2) and dried over sodium sulfate. It was then filtered to obtain the filtrate and concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:30) to give the title compound (0.7 g, 74% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.81 (s, 1H), 7.37-7.29 (m, 2H), 7.02 (t, J=7.3 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.18 (s, 1H), 5.15 (br s, 1H), 4.65 (br s, 1H), 4.26-4.17 (m, 4H), 3.96-3.87 (m, 2H), 3.86-3.74 (m, 3H), 3.72-3.51 (m, 7H), 3.47-3.39 (m, 2H), 3.08 (quintet, J = 8.4 Hz, 1H), 2.54-2.36 (m, 2H), 2.03-1.75 (m, 5H), 1.32 (s, 8H), 1.16 (dd, J = 3.1, 6.4 Hz, 6H).

Isopropylcarbamic acid (1S,3R)-3-((3S)-5-(1-methyl-3-((non-8-yn-1-yloxy)methyl)- 1H-pyrazole-5-carboxamido)pyrazolidin-3-yl)cyclopentyl ester (Intermediate EW)

To a solution of 1-methyl-3-((non-8-yn-1-yloxy)methyl)-1H-pyrazole-5-carboxylic acid (150 mg, 539 μmol, Intermediate AR) and (1S,3R)-3-((3S)-5-aminopyrazolidin-3-yl)cyclopentylisopropylcarbamate (166 mg, 539 μmol, Intermediate ED) in MeCN (3 mL) was added DIEA (348 mg, 2.69 mmol) and T ₃ P (1.03 g, 1.62 mmol, 50% solution). The mixture was then stirred at 60 °C for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (2 mL) at 20 °C and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (2 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/4 to 1/3) to give the title compound (100 mg, 30% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 569.5 (M+H) ⁺ .

4-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- 3-Methylbenzene-1-sulfonyl chloride (Intermediate EX)

Step 1-2-((4-(phenylmethylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentyl-5-methylpyrido[2, 3-d]pyrimidin-7(8H)-one

To a solution of 6-bromo-2-chloro-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.46 mmol, CAS# 1016636-76-2) and 4-(phenylmethylthio)-2-methylaniline (502 mg, 2.19 mmol, intermediate M) in IPA (10 mL) was added TFA (1.66 g, 14.6 mmol), and then the mixture was stirred at 80 °C for 12 hr. Upon completion, the reaction mixture was quenched with NaHCO ₃ solution (20 mL) and extracted with EtOAc (40 mL×3). The organic layer was washed with brine (25 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=15/1 to 3/1) to give the title compound (440 mg, 56% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ=9.40 (s, 1H), 8.88 (s, 1H), 7.43-7.20 (m, 8H), 5.82-5.62 (m, 1H), 4.23 (s, 2H), 2.55 (s, 3H), 2.17 (s, 3H), 2.10-2.04 (m, 2H), 1.62 (br s, 4H), 1.40 (br s, 2H); LC-MS (ESI ⁺ ) m/z 536.9 (M+H) ⁺ .

Step 2-4-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) Amino)-3-methylbenzene-1-sulfonyl chloride

To a solution of 2-((4-(phenylmethylthio)-2-methylphenyl)amino)-6-bromo-8-cyclopentyl-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one (400 mg, 747 μmol) in AcOH (10 mL) and HCl (0.3 mL) was added NCS (399 mg, 2.99 mmol) at 0°C, and then the mixture was stirred at 0-25°C for 30 min. After completion, the reaction mixture was quenched with water (20 mL) and extracted with DCM (10 mL×3). The organic layer was washed with brine (25 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (300 mg, 79% yield) as a pink solid. ¹ H NMR (400MHz, DMSO-d6) δ = 9.45 (s, 1H), 8.89 (s, 1H), 7.48 (s, 1H), 7.44-7.35 (m, 2H), 5.83-5.72 (m, 1H), 2.55 (s, 3H), 2.23 (s, 3H), 2.14-2.03 (m, 2H), 1.99(s,2H),1.91(s,1H),1.77-1.62(m,4H),1.51-1.39(m,2H),1.26-1.13(m,2H); LC-MS(ESI ⁺ )m/z 513.2(M+H) ⁺ .

Benzyl 3,6,9,12-tetraoxapentadeca-14-yn-1-ylcarbamate (Intermediate EY)

To a solution of 3,6,9,12-tetraoxapentadeca-14-yn-1-amine (3 g, 12.97 mmol, CAS#1013921-36-2) in DCM (20 mL) was added TEA (1.44 g, 14.3 mmol). A solution of benzyl chloroformate (2.43 g, 14.3 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0-20 °C for 12 h. Upon completion, the reaction mixture was quenched by the addition of NaHCO ₃ (sat., aq, 20 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (20 mL×3), dried over Na ₂ SO ₄ and evaporated. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (4.4 g, 93% yield) as a white gum. ¹ H NMR (400MHz, DMSO-d6) δ7.39-7.28(m,5H),7.24(br t,J＝5.6Hz,1H),5.01(s,2H),4.13(d,J＝2.4Hz,2H),3.55-3.52(m,4H),3.50(s,8H),3.44-3.38(m,3 H),3.19-3.08(m,2H).

3-(5-(1-amino-3,6,9,12-tetraoxapentadeca-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzene (d)imidazol-1-yl)piperidin-2,6-dione (Intermediate EZ)

Step 1-(15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d] Benzyl imidazol-5-yl)-3,6,9,12-tetraoxapentadeca-14-yn-1-yl)carbamate

To a _solution of benzyl 3,6,9,12-tetraoxapentadeca-14-yn-1-ylcarbamate (2.2 g, 6.02 mmol, intermediate EY) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (3.05 g, 9.03 mmol, intermediate J) in THF (10 mL) and ACN (10 mL) was added XPhos Pd G3 (1.53 g, 1.81 mmol) and Cs ₂ CO ₃ (11.8 g, 36.1 mmol) under N 2. The mixture was stirred at 20-60 °C for 12 h. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl (20 mL) and extracted with EtOAC (30 mL×2). The combined organic layers were washed with brine (10 mL x 3), dried over Na ₂ SO ₄ and evaporated. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 28%-55%, 18 min) to give the title compound (2.56 g, 68% yield) as a white gum. ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.12(s,1H),7.37-7.29(m,6H),7.29-7.25(m,1H),7.19-7.11(m,2H),5.39(dd,J＝5.6,12.8Hz,1H),5.01(s,2H),4.39(s,2H),3.66-3.61(m,2H) ,3.60-3.55(m,2H),3.54-3.48(m,8H),3.41(t,J＝6Hz,2H),3.34(s,3H),3.14(q,J＝5.6Hz,2H),2.94-2.83(m,1H),2.76-2.57(m,2H),2.08-2.00(m, 1H).

Step 2-3-(5-(1-amino-3,6,9,12-tetraoxapentadeca-15-yl)-3-methyl-2-oxo-2,3-dihydro- 1H-Benzo[d]imidazol-1-yl)piperidine-2,6-dione

To _a solution of N-[2-[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]prop-2-ynyloxy]ethoxy]ethoxy]ethoxy]ethyl]carbamic acid benzyl ester (1 g, 2 mmol) in THF (5 mL) was added Pd/C (400 mg, 642 μmol, 10 wt %) under N. The suspension was degassed in vacuo and purged with _H several times. The reactants were stirred at 20 °C under _H atmosphere (15 PSI) for 17 h. Upon completion, the mixture was filtered and concentrated to give the title compound (690 mg) as a white gum. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.11-7.97(m,1H),7.77(br s,1H),7.44(s,1H),7.24(d,J＝7.6Hz,1H),7.21-7.12(m,2H),7.05-6.97(m,1H),6.90-6.80(m,1H ),5.33(br dd,J＝5.2,12.6Hz,1H),4.81(br dd,J＝4.8,10.8Hz,1H),3.54-3.45(m,8H),3.39(br d,J＝4.4Hz,2H),3.34(br s,3H),2.70-2.58(m,3H),2.18(s,1H),2.04-1.93(m,1H),1.81(br s,2H),1.36(s,2H).

Isopropylcarbamic acid (1S,3R)-3-(1-(tert-butyl)-5-(1-(undec-10-yn-1-yl)-1H-pyrazole-4- (Formylamino)-1H-pyrazol-3-yl)cyclopentyl ester (Intermediate FA)

To a solution of 1-undec-10-ynylpyrazole-4-carboxylic acid (500 mg, 1.91 mmol, intermediate Y) and [(1S,3R)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (490 mg, 1.59 mmol, intermediate CB) in ACN (8 mL) was added DIEA (1.03 g, 7.94 mmol, 1.38 mL) and T ₃ P (3.03 g, 4.76 mmol) dropwise in one portion at 20° C. The mixture was then stirred at 60° C. for 10 h. Upon completion, the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The product was purified by flash silica gel chromatography ( 4g The residue was purified by HPLC-MS/MS (ESI ^{+) (HPLC-MS/MS) (50 mL/min, gradient eluent 0 to 30% ethyl acetate in petroleum ether) to give the title compound as a white solid (325 mg, 37% yield). LC-MS (ESI+} ) m/z 553.4 (M+H) ⁺ .

(2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecane-1- Acyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (Intermediate FB)

Step 1-((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl) tert-Butyl pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecayl)carbamate

A solution of (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butyryl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (233 mg, 542 μmol, CAS#1448189-80-7), 2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]acetic acid (200 mg, 651 μmol, CAS#462100-06-7), DIEA (350 mg, 2.71 mmol) and HATU (247 mg, 651 μmol) in DMF (10 mL) was added at 0°C. The mixture was stirred at 25°C for 12 h. Upon completion, the mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL x 3), dried over _Na2SO4 , and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , DCM/MeOH = 10: ₁ to 2:1) to give the title compound (380 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m/z 620.4 (M+H) ⁺ .

Step 2-(2S,4R)-1-((S)-14-amino-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azadecanoyl Tetra-1-yl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Tert-butyl ((S)-13-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carbonyl)-14,14-dimethyl-11-oxo-3,6,9-trioxa-12-azapentadecanyl)carbamate (0.19 g, 260 μmol) in HCl/dioxane (2 mL) was stirred at 25° C. for 10 min. Upon completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 83% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ＝11.08-11.04(m,1H),9.51(s,1H),8.73(s,1H),7.77-7.60(m,5H),7.02-6.84(m,3H),6.34-6.31(d,J＝9.2,1H),5.69-564 (m,1H),5.35-5.30(m,1H),3.50-3.48(m,6H),3.47-3.41(m,5H),3.37-3.30(m,6H),2.90(s,2H),2.63-2.52(m,4H),2.32(s,3H),1.81-1.78(m,5 H),1.64-1.43(m,6H).

(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy]ethoxy [4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine- 2-Formamide (Intermediate FC)

Step 1-N-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazole-5- 1-(2 ... tert-Butyl]ethoxy]ethoxy]ethyl]carbamate

To a solution of 2-[2-[2-[2-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxy]ethoxy]ethoxy]acetic acid (568 mg, 1.62 mmol, CAS#876345-13-0), (2S,4R)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide (580 mg, 1.35 mmol, CAS#1448189-80-7) in DMF (10 mL) was added DIEA (870 mg, 6.74 mmol) and HATU (614.64 mg, 1.62 mmol) at 0°C. The mixture was then stirred at 25°C for 2 hr. Upon completion, the reaction mixture was quenched with water 20 mL at 0°C and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saline solution (10 mL x 3), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give the title compound (800 mg, 78% yield) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d6) δ=9.01-8.96 (m, 1H), 8.59 (br t, J=5.6 Hz, 1H), 7.47-7.42 (m, 1H), 7.42-7.36 (m, 4H), 7.36-7.36 (m, 1H), 6.73 (br t,J＝4.8Hz,1H),5.15(d,J＝3.6Hz,1H),4.56(d,J＝9.2Hz,1H),4.37-4.36(m,1H),4.48-4.36(m,1H),4.29-4.20(m,1H),4.01-3.90(m,2H),3.70-3.43 (m,16H),3.17(d,J＝5.2Hz,1H),3.04(q,J＝5.6Hz,2H),2.46-2.43(m,3H),2.06(br dd, J＝7.6, 12.8Hz, 1H), 1.90 (ddd, J＝4.0, 8.4, 12.8Hz, 1H), 1.36 (s, 9H), 0.99-0.89 (m, 9H); LC-MS (ESI ⁺ ) m/z 764.4 (M+H) ⁺ .

Step 2-(2S,4R)-1-[(2S)-2-[[2-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethoxy 4-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidone]-3,3-dimethyl-butyryl]-4-hydroxy-N-[[4-(4-methylthiazol-5-yl)phenyl]methyl]pyrrolidone] Pyrrolidine-2-carboxamide

To a solution of tert-butyl N-[2-[2-[2-[2-[2-[[(1S)-1-[(2S,4R)-4-hydroxy-2-[[4-(4-methylthiazol-5-yl)phenyl]methylcarbamoyl]pyrrolidine-1-carbonyl]-2,2-dimethyl-propyl]amino]-2-oxo-ethoxy]ethoxy]ethoxy]ethoxy]ethyl]carbamate (400 mg, 524 μmol) in DCM (2 mL) was added HCl/dioxane (4 mL, 4 M) and the mixture was then stirred at 25 °C for 1.5 h. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (200 mg, 55% yield, HCl) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ = 9.02 (s, 1H), 8.62 (t, J = 6.0Hz, 1H), 8.04-7.75 (m, 3H), 7.52-7.46 (m, 1H), 7.40 (s, 4H), 4.56 (d, J = 9.4Hz, 1H), 4.47-4.37 (m, 2H),4.36(br s,1H),4.30-4.21(m,1H),3.98(s,2H),3.63-3.57(m,8H),3.56-3.52(m,8H),2.98-2.92(m,2H),2.45(s,3H),2.13-2.01(m,1H),1.90(ddd,J＝4.4 ,8.8,13.2Hz,1H),0.98-0.91(m,9H). LC-MS(ESI ⁺ )m/z 664.3(M+H) ⁺ .

3-[5-[3-(2-azidoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin-2,6-diol Ketone (Intermediate FD)

Step 1-3-[5-[3-(2-hydroxyethoxy)prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidin Pyridine-2,6-dione

To a solution of 2-prop-2-ynyloxyethanol (500 mg, 4.99 mmol, CAS#3973-18-0) and 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (2.03 g, 5.99 mmol, Intermediate J) in ACN (10 mL) and THF (10 mL) was added XPhos Pd G3 (845 mg, 999 μmol) and Cs ₂ CO ₃ (4.88 g, 14.9 mmol). The mixture was stirred at 60 °C under nitrogen atmosphere for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl solution (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give the title compound (550 mg, 31% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ=11.1 (s, 1H), 7.33 (s, 1H), 7.20-7.09 (m, 2H), 5.39 (dd, J=5.6, 13.2 Hz, 1H), 4.78-4.52 (m, 1H), 4.39 (s, 2H), 4.03 (q, J=7.2 Hz, 1H), 3.56-3.53 (m, 3H), 3.34 (s, 4H), 2.77-2.56 (m, 4H); LC-MS (ESI ⁺ ) m/z 358.1 (M+H) ⁺ .

Step 2-3-[5-[3-(2-hydroxyethoxy)propyl]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2-yl 6-Dione

To a solution of 3-[5-[3-(2-hydroxyethoxy)prop-1-ynyl]-3-methyl-2-oxo-benzoimidazol _- 1-yl]piperidine-2,6-dione (550 mg, 1.5 mmol) in THF (6 mL) under H 2 was added PtO ₂ (69.9 mg, 308 μmol) and the mixture was stirred at 25 ° C for 2 h. After completion, the reaction mixture was filtered through celite. The organic phase was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give the title compound (300 mg, 54% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d6) δ = 11.08 (s, 1H), 7.04 (d, J = 1.2Hz, 1H), 7.00 (d, J = 8.4Hz, 1H), 6.87 (dd, J = 1.6, 8.4Hz, 1H), 5.33 (dd, J = 5.6, 12.8Hz, 1H), ^4.63-4.51 LC-MS )m/z 362.0(M+H) ⁺ .

Step 3-4-methylbenzenesulfonic acid 2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole oxazol-5-yl]propoxy]ethyl ester

To _a solution of 3-[5-[3-(2-hydroxyethoxy)propyl]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (150 mg, 415 μmol) and TEA (126 mg, 1.25 mmol, 173 μL) in DCM (3 mL) at 0 °C under N2 was added TosCl (119 mg, 623 μmol) and DMAP (10.1 mg, 83.0 μmol). The mixture was then stirred at 25 °C for 12 h. Upon completion, the reaction mixture was quenched with _NaHCO3 solution (30 mL) at 0 °C and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (10 mL×3), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 0/1) to give the title compound (179 mg, 84% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d6) δ=11.08 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.09-6.92 (m, 2H), 6.84 (d, J=8.4 Hz, 1H), 5.33 (dd, J=5.2, 12.8 Hz, 1H), 4.17-4.10 (m, 2H), 3.58-3.50 (m, 2H), 3.30 (br s,3H),2.94-2.85(m,1H),2.76-2.62(m,2H),2.60-2.55(m,2H),2.53-2.51(m,2H),2.40(s,3H),2.05-1.99(m,1H),1.79-1.67(m,2H); LC-MS(ESI ⁺ )m /z 516.4(M+H) ⁺ .

Step 4-3-[5-[3-(2-azidoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine- 2,6-Dione

To _a solution of 4-methylbenzenesulfonic acid 2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]propoxy]ethyl ester (170 mg, 330 μmol) in DMF (2 mL) was added NaN ₃ (23.6 mg, 362 μmol) at 0° C. under N 2. The mixture was then stirred at 40° C. for 12 h. Upon completion, the reaction was poured into NaHCO ₃ solution (10 mL) at 0° C. and extracted with ethyl acetate (10 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over Na ₂ SO ₄ , then filtered to give a filtrate and concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (70 mg, 53% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 387.1 (M+H) ⁺ .

tert-Butyl 6-(2-(Tosyloxy)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate FE)

Step 1-tert-Butyl 6-(2-(tert-butoxy)-2-oxoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 46.8 mmol, CAS# 1147557-97-8), tert-butyl 2-bromoacetate (13.7 g, 70.3 mmol) and tetrabutylammonium hydrogen sulfate (1.59 g, 4.69 mmol) in toluene (10 mL) and H ₂ O (1 mL) was added NaOH (9.38 g, 234 mmol) and the mixture was stirred at rt for 12 hr. Upon completion, the reaction mixture was quenched with NH ₄ Cl aqueous solution 100 mL at 0° C. and then diluted with H ₂ O (100 mL) and extracted with EtOAc (150 mL×2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (11 g, 72% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=3.92-3.84 (m, 1H), 3.83-3.77 (m, 6H), 2.47-2.35 (m, 2H), 2.19-2.05 (m, 2H), 1.40 (s, 9H), 1.35 (s, 9H); LC-MS (ESI ⁺ ) m/z 328.2 (M+H) ⁺ .

Step 2-tert-Butyl 6-(2-hydroxyethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-(2-tert-butoxy-2-oxo-ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (10 g, 30.5 mmol) in THF (150 mL) was added LiAlH ₄ (2.32 g, 61.0 mmol). The mixture was stirred at 0° C. for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (4 mL) and NaOH (15%, 4 mL) at 0° C. and then stirred at 25° C. for 30 min. The mixture was then filtered and concentrated under reduced pressure to give the title compound as a yellow oil (5 g). LC-MS (ESI ⁺ ) m/z 258.2 (M+H) ⁺ .

Step 3-tert-Butyl 6-(2-(Tosyloxy)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-(2-hydroxyethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (5 g, 20 mmol) in DCM (50 mL) was added TEA (5.90 g, 58.2 mmol), TosCl (4.45 g, 23.3 mmol) and DMAP (474 mg, 3.89 mmol). The mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was quenched with aqueous NH ₄ Cl solution (50 mL), and then diluted with H ₂ O (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 4/1) to give the title compound (1.8 g, 22.% yield) as a yellow oil. LC-MS(ESI ⁺ )m/z 356.2(M+H) ⁺ .

3-(5-(1-(2-(2-azaspiro[3.3]hept-6-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2, 3-Dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FF)

Step 1-6-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] imidazol-5-yl)piperidin-1-yl)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (300 mg, 876 μmol, Intermediate DB) and tert-butyl 6-[2-(p-tolylsulfonyloxy)ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (360 mg, 876 μmol, Intermediate FE) in ACN (3 mL) was added K ₂ CO ₃ (605 mg, 4.38 mmol) and KI (14.5 mg, 87.6 μmol). The mixture was stirred at 60 °C for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give the title compound (80 mg, 15% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 582.4 (M+H) ⁺ .

Step 2-3-(5-(1-(2-(2-azaspiro[3.3]hept-6-yloxy)ethyl)piperidin-4-yl)-3-methyl-2- Oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 6-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (80 mg, 140 μmol) in DCM (2 mL) was added TFA (15.6 mg, 137 μmol). The mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (75 mg, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 482.4 (M+H) ⁺ .

4-Propan-2-ynyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester (Intermediate FG)

To a solution of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (400 mg, 1.56 mmol, CAS# 930785-40-3), K ₂ CO ₃ (646 mg, 4.68 mmol) in THF (40 mL) was added 3-bromoprop-1-yne (243 mg, 1.64 mmol). The reaction mixture was stirred at 20 °C for 24 hr. Upon completion, the reaction mixture was concentrated in vacuo. The residue was diluted with H ₂ O (30 mL) and extracted with EA (3×20 mL). The organic layer was washed with brine (2×15 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (450 mg, 97% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ3.82-3.65(m,4H),3.27(d,J＝2.4Hz,2H),3.22-3.10(m,2H),2.55-2.50(m,2H),2.37(s,2H),2.29-2.26(m,1H),1.99-1.90(m ,2H),1.53-1.45(m,11H).

3-(4-(Hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dihydro- Ketone (Intermediate FH)

Step 1-3-(4-(Hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-Dione

To a solution of 1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-4-carbaldehyde (7.00 g, 24.3 mmol, intermediate BZ) and HOAc (4.39 g, 73.1 mmol) in DMF (50 mL) and THF (50 mL) was added NaBH ₃ CN (6.13 g, 97.4 mmol) portionwise at 60° C. and then the mixture was stirred at 60° C. for 2 hours. Upon completion, the reaction was quenched with 5 mL of water and filtered and the filtrate was concentrated. The residue was purified by reverse phase (FA) to give the title compound (5.00 g, 70% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 7.13-6.89 (m, 3H), 5.38 (d, J = 5.4, 12.4Hz, 1H), 4.74 (s, 2H), 3.62 (s, 3H), 2.95-2.86 (m, 1H), 2.78-2.60 (m, 2H) ,2.10-1.95(m,1H).

Step 2-3-(4-(Hydroxymethyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine- 2,6-Dione

To a solution of 3-[4-(hydroxymethyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (5.00 g, 17.2 mmol) and pyridine (273 mg, 3.46 mmol) in THF (30 mL) and DCM (30 mL) was added _SOCl2 (6.17 g, 51.8 mmol), and then the mixture was stirred at 20°C for 12 hr. After completion, the reaction was concentrated to give the title compound (8.00 g, 90% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08 (s, 1H), 7.19-6.99 (m, 3H), 5.32 (dd, J = 5.2, 12.4Hz, 1H), 5.03 (s, 2H), 3.65 (s, 3H), 2.92-2.80 (m, 1H), 2.73-2.59 (m, 2H) ,2.10-1.98(m,1H).

Benzyl 4-(4-(prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (Intermediate FI)

Step 1-4-(1-((Benzyloxy)carbonyl)piperidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester

To a solution of benzyl 4-oxopiperidine-1-carboxylate (5 g, 20 mmol, CAS#19099-93-5) and tert-butyl piperazine-1-carboxylate (4.77 g, 21.4 mmol, CAS#57260-71-6) in DMSO (25 mL) and THF (25 mL) was added KOAc (6.31 g, 64.31 mmol) Molecular sieves (1 g) and HOAc (3.86 g, 64.3 mmol), and the mixture was stirred at 0°C for 30 min. Then NaBH(OAc) ₃ (13.63 g, 64.31 mmol) was added and the mixture was stirred at 0-20°C for 12 h. The reaction mixture was quenched with H ₂ O (50 mL) at 0°C, and then diluted with EtOAc (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were washed with sat. NaCl (50 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (4 g, 46% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ＝7.45-7.22(m,7H),5.06(s,3H),4.01(br d,J＝13.2Hz,2H),3.78-3.59(m,2H),3.46-3.37(m,1H),3.06(br s,1H),2.92-2.63(m ,2H),2.41(br s,5H),1.91(s,1H),1.71(br d,J＝12.2Hz,3H),1.38(s,9H),1.33-1.20(m,4H); LC-MS(ESI ⁺ )m/z 404.5(M+H) ⁺ .

Step 2-4-(Piperazin-1-yl)piperidine-1-carboxylic acid benzyl ester

To a solution of tert-butyl 4-(1-((benzyloxy)carbonyl)piperidin-4-yl)piperazine-1-carboxylate (100 mg, 300 μmol) in DCM (1 mL) was added TFA (28.2 mg, 247 μmol). The mixture was stirred at 25 °C for 4 hr. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (70 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 304 (M+H) ⁺

Step 3-4-(4-(Propan-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-(piperazin-1-yl)piperidine-1-carboxylate (2.3 g, 7.6 mmol) and 3-bromoprop-1-yne (811.63 mg, 6.82 mmol, CAS#106-96-7) in ACN (25 mL) was added K ₂ CO ₃ (10.4 g, 75.8 mmol). The mixture was stirred at 20 °C under N ₂ atmosphere for 10 h. The reaction mixture was quenched with H ₂ O (25 mL) at 25 °C and then diluted with EtOAc (25 mL) and extracted with EtOAc (25 mL×3). The combined organic layers were washed with sat. NaCl (25 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (0.05% NH 3 H 2 O)-ACN]; B%: 25%-55%, 10 min) to give the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 8.20 (s, 2H), 7.37-7.33 (m, 3H), 5.76 (s, 1H), 5.12-5.00 (m, 2H), 4.62-4.46 (m, 1H), 4.01 (br d, J = 13.0Hz, 2H), 3.53 (br s, 1H), 3.23(d,J＝2.4Hz,1H),2.94-2.71(m,3H),2.45(br s,5H),1.75(br d,J＝10.4Hz,3H),1.29(dq,J＝3.8,11.8Hz,2H); LC-MS(ESI ⁺ )m/z 342.4(M+H) ⁺ .

3-(3-methyl-2-oxo-5-(3-(4-(piperidin-4-yl)piperazin-1-yl)propyl)-2,3-dihydro-1H-benzo [d]Imidazol-1-yl)piperidine-2,6-dione (Intermediate FJ)

Step 1-4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] [imidazol-5-yl)prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-(4-(prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (270 mg, 790 μmol, Intermediate FI) and 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (320 mg, 948 μmol, Intermediate J) in THF (1.5 mL) and ACN (1.5 mL) was added XPhos Pd G3 (200 mg, 237 μmol) and Cs ₂ CO ₃ (1.29 g, 3.95 mmol). The mixture was stirred at 60 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl (5 mL) at 0 °C, and then diluted with EtOAc (5 mL) and extracted with EtOAc (5 mL×3). The combined organic layers were washed with sat. NaCl (5 mL x 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA conditions) to give the title compound (380 mg, 80% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 11.11 (s, 1H), 8.14 (s, 1H), 7.43-7.27 (m, 6H), 7.19-7.06 (m, 2H), 5.38 (dd, J = 5.3, 12.8Hz, 1H), 5.05 (s, 2H), 4.01 (br d, J = 13.0 Hz,3H),3.48(s,5H),2.93-2.73(m,4H),2.73-2.58(m,3H),2.44-2.30(m,2H),2.10-1.94(m,1H),1.75(br d,J＝11.2Hz,2H),1.28(dq,J＝4.0,11.8Hz,2H ); LC-MS(ESI ⁺ )m/z 599.3(M+H) ⁺ .

Step 2-3-(3-methyl-2-oxo-5-(3-(4-(piperidin-4-yl)piperazin-1-yl)propyl)-2,3-dihydro- 1H-Benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of benzyl 4-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)piperazin-1-yl)piperidine-1-carboxylate (310 mg, 520 μmol) in THF (15 mL) was added Pd/C (548 mg, 517 μmol, 10 wt%). The mixture was stirred at 20 °C under _H2 atmosphere for 4 h. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18150*25mm*5μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 0%-20%, 10 min) to give the title compound (80 mg, 33% yield) as a white oil. LC-MS(ESI ⁺ )m/z 469.4(M+H) ⁺ .

3-(4-(3-(1-oxa-4,9-diazaspiro[5.5]undec-4-yl)propyl)-3-methyl-2-oxo-2,3-dioxo- H-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate FK)

Step 1-4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]propane-2- [alkynyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-prop-2-ynyl-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (450 mg, 1.53 mmol, Intermediate FG), 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (344 mg, 1.02 mmol, Intermediate H) in DMF (5 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (143 mg, 203 μmol), CuI (38.8 mg, 203 μmol) and Cs ₂ CO ₃ (1.33 g, 4.08 mmol). The reaction mixture was stirred at 80 °C for 3 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was purified by reverse phase: (0.1% FA) to give the title compound (400 mg, 71% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.12(s,1H),7.20-7.09(m,2H),7.06-6.99(m,1H),5.47-5.32(m,1H),3.70-3.62(m,5H),3.61-3.54(m,4H),3.11-2.99(m, 2H),2.94-2.83(m,1H),2.78-2.68(m,1H),2.66-2.57(m,1H),2.43-2.35(m ,2H),2.08-1.98(m,1H),1.89-1.75(m,2H),1.46-1.28(m,13H),LC-MS(ESI ⁺ )m/z 552.4(M+H) ⁺ .

Step 2-4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]propane tert-Butyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate

To a solution of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]prop-2-ynyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 181 μmol) in THF (10.0 mL) was added Pd/C (50 mg) and Pd(OH) ₂ /C (50 mg). The reaction mixture was stirred at 25 °C under H ₂ (15 psi) for 3 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 99% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.09(s,1H),7.00-6.93(m,2H),6.92-6.88(m,1H),5.43-5.31(m,1H),3.64-3.59(m,3H),3.57(s,3H),3.55-3.49(m,1H),3.13-2.98(m,2H),2 .96-2.83(m,3H),2.76-2.68(m,1H),2.65-2.60(m,1H),2.32-2.25(m,3H ),2.24-2.19(m,2H),2.05-1.96(m,1H),1.85-1.68(m,5H),1.45-1.40(m, 2H),1.36(s,9H).

Step 3-3-[3-methyl-4-[3-(1-oxa-4,9-diazaspiro[5.5]undec-4-yl)propyl]-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]propyl]-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (100 mg, 179 μmol) in DCM (3.00 mL) was added HCl/dioxane (4.00 M, 3.00 mL). The reaction mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (88.0 mg, 99% yield, HCl salt) as a yellow solid. LC-MS (ESI ⁺ ) m/z 456.2 (M+H) ⁺ .

3-[3-methyl-2-oxo-5-[3-(4-piperidinyloxy)propyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate FL)

Step 1-4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]propane-2- Alkynyloxy]

Piperidine-1-carboxylic acid tert-butyl ester

To a mixture of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl ₎ piperidine-2,6-dione (350 mg, 1.04 mmol, Intermediate J) and tert-butyl 4-prop-2-ynyloxypiperidine-1-carboxylate (371 mg, 1.55 mmol, synthesized via step 1 of Intermediate FW) in DMF (20 mL) at 25 °C under N2 were added Pd(PPh3) _2Cl2 (72.6 mg, 103 μmol), CuI (39.4 mg, 207 μmol), _Cs2CO3 (1.35 g, 4.14 mmol) and 4-prop- _2- ynyloxypiperidine-1-carboxylate (371 mg, 1.55 mmol, synthesized via step ₁ of Intermediate FW) in _DMF (20 mL) in one portion. Molecular sieves (200 mg, 1.04 mmol). The reaction mixture was stirred at 80 ° C for 2 hours. After completion, the reaction mixture was quenched by adding water (0.5 mL) at 25 ° C, and then extracted with EA (3 × 20 mL). The combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA conditions) to give the title compound (300 mg, 58% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.14 (s, 1H), 7.23-7.17 (m, 1H), 7.12 (d, J = 1.2Hz, 1H), 6.75 (d, J = 8.1Hz, 1H), 5.24-5.17 (m, 1H), 4.43 (s, 2H), 3.85-3.72 (m, 3H), 3.43(s,3H),3.18-3.09(m,2H),3.01-2.92(m,1H),2.90-2.67(m,2H),2.30 -2.20(m,1H),1.94-1.86(m,2H),1.64-1.57(m,2H),1.47(s,9H); LC-MS(ESI ⁺ )m/z 519.3(M+Na) ⁺ .

Step 2-4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]propoxy tert-Butyl]piperidine-1-carboxylate

To a _solution of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]prop-2-ynyloxy]piperidine-1-carboxylate (300 mg, 604 μmol) in THF (4 mL) under N2 was added Pd/C (50 mg, 10 wt%) and Pd(OH) ₂ /C (50 mg, 10 wt%). The suspension was degassed in vacuo and purged with _H2 three times. The mixture was stirred at 25 °C under _H2 (15 psi) for 2 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (FA conditions) to give the title compound (300 mg, 84% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.24 (s, 1H), 6.95-6.85 (m, 2H), 6.73 (d, J = 8.2Hz, 1H), 5.26-5.18 (m, 1H), 3.81-3.73 (m, 2H), 3.49-3.42 (m, 6H), 3.15-3.05 (m, 2 H),2.99-2.82(m,2H),2.75(t,J＝7.6Hz,3H),2.28-2.19(m,1H),1.95-1.77(m,4H),1.53(d,J＝8.8Hz,2H),1.47(s,9H); LC-MS(ESI ⁺ )m/z 401.0(M+H-100 ) ⁺ .

Step 3-3-[3-methyl-2-oxo-5-[3-(4-piperidinyloxy)propyl]benzimidazol-1-yl]piperidin-2-yl, 6-Dione

To a mixture of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]propoxy]piperidine-1-carboxylate (270 mg, 539 μmol) in DCM (4 mL) was added TFA (1.84 g, 16.2 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 2 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (TFA conditions) to give the title compound (162 mg, 58% yield, TFA salt) as a yellow solid. LC-MS (ESI+) m/z 401.0 (M+H) ⁺ .

tert-Butyl 6-(2-aminoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate FM)

Step 1-6-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid Tert-butyl ester

To a solution of tert-butyl 6-[2-(p-tolylsulfonyloxy)ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (1.8 g, 4.4 mmol, intermediate FE) in DMF (20 mL) was added potassium (1,3-dioxoisoindolin-2-yl) (1.22 g, 6.56 mmol). The mixture was stirred at 80 °C for 12 h. Upon completion, the reaction mixture was treated with H ₂ O (20 mL) at 20 °C and then filtered under reduced pressure to give the title compound (1 g) as a white solid. LC-MS (ESI ⁺ ) m/z 387.1 (M+H) ⁺ .

Step 2-tert-Butyl 6-(2-aminoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (400 mg, 1 mmol) in EtOH (6 mL) was added NH ₂ NH ₂ .H ₂ O (259 mg, 5.18 mmol). The mixture was stirred at 50 °C for 2 h. Upon completion, the residue was purified by recrystallization from DCM (10 mL) at 20 °C, and then filtered and concentrated under reduced pressure to give a residue. The residue was purified by recrystallization from DCM (10 mL) at 0 °C, and then filtered and dried under reduced pressure to give the title compound (240 mg, 90% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 257.1 (M+H) ⁺ .

N-(2-(2-azaspiro[3.3]hept-6-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydropyridine (2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide (Intermediate FN)

Step 1-6-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) tert-Butyl (amino)-3-methylphenylsulfonylamino)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-(2-aminoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 800 μmol, Intermediate FM) in DCM (5 mL) was added DIEA (302 mg, 2.34 mmol) and 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (353 mg, 780 μmol, Intermediate CW). The mixture was stirred at 20 °C for 10 min. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (400 mg) as a yellow oil. LC-MS (ESI ⁺ ) m/z 673.3 (M+H) ⁺ .

Step 2-6-(2-(4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- tert-Butyl (3-methylphenylsulfonylamino)ethoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert _- butyl 6-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 742 μmol) and TEA (191 mg, 1.90 mmol) in THF (10 mL) under N2 was added TEA (191.98 mg, 1.90 mmol) and Pd/C (10 wt%, 500 mg). The suspension was degassed in vacuo and purged with _H2 several times. The mixture was then stirred under _H2 (15 psi) at 20 °C for 0.5 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (300 mg) as a yellow solid. LC-MS(ESI ⁺ )m/z 639.4(M+H) ⁺ .

Step 3-N-(2-(2-azaspiro[3.3]hept-6-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydro- (2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide

To a solution of tert-butyl 6-[2-[[4-[(8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (150 mg, 234.82 μmol) in DCM (4 mL) was added TFA (693 mg, 6.08 mmol). The mixture was stirred at 20 °C for 0.5 h. Upon completion, the reaction mixture was filtered under reduced pressure to give the title compound (150 mg, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 539.2 (M+H) ⁺ .

(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- 1-(4 ...2-methyl-1-nitropropylenic acid)aldehyde (intermediate FO

Step 1 -3-(5-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-3-methyl-2-oxo- 2,3-Dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

A mixture of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (3 g, 8.87 mmol, intermediate J), tert-butyl-dimethyl-prop-2-ynyloxy-silane (4.53 g, 26.6 mmol), TEA (4.49 g, 44.3 mmol), Pd(PPh ₃ ) ₄ (1.03 g, 887 μmol) and CuI (337 mg, 1.77 mmol) in DMSO (50 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 85 ° C under N ₂ atmosphere for 12 h. After completion, the reaction mixture was diluted with H ₂ O (200 mL) and extracted with EtOAc (200 mL×2). The combined organic layers were washed with aqueous NaCl solution (200 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to give the title compound (2 g, 50% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 428.2 (M+H) ⁺ .

Step 2-3-(5-(3-hydroxyprop-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole oxazol-1-yl)piperidin-2,6-dione

To a solution of 3-[5-[3-[tert-butyl(dimethyl)silanyl]oxyprop-1-ynyl]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (300 mg, 700 μmol) in DMSO (5 mL) was added CsF (532 mg, 3.51 mmol). The mixture was stirred at 20 °C for 2 h. Upon completion, the reaction mixture was quenched with HCl (1 M, 10 mL) at 0 °C, and then diluted with H ₂ O (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with aqueous NaCl solution (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (200 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 314.1 (M+H) ⁺ .

Step 3-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole oxazol-5-yl)propynyl aldehyde

To a solution of 3-[5-(3-hydroxyprop-1-ynyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (200 mg, 638 μmol) in DCM (5 mL) and DMSO (2 mL) was added DMP (541 mg, 1.28 mmol) at 0°C. The mixture was stirred at 25°C for 12 hr. Upon completion, the reaction mixture was diluted with H ₂ O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with aqueous NaCl solution (20 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (120 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 312.1 (M+H) ⁺ .

tert-Butyl 9-(2-(Tosyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (Intermediate FP)

Step 1-9-Hydroxy-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

A solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (3 g, 10 mmol, CAS#873924-08-4) in THF (30 mL) was added with NaBH ₄ (636 mg, 16.8 mmol) in several portions at 0° C., and then the mixture was stirred at 20° C. for 12 h. Upon completion, the reaction mixture was quenched with aqueous NH ₄ Cl solution (50 mL) at 20° C., and then diluted with EtOAc (10 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (3 g, 99% yield) as a yellow solid.

Step 2-tert-Butyl 9-(2-(tert-butoxy)-2-oxoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate (3 g, 11.1 mmol) in THF (30 mL) was added NaH (668 mg, 16.7 mmol, 60% dispersion in mineral oil) at 0°C, and the mixture was stirred at 0°C for 1 h. Then tert-butyl 2-bromoacetate (3.26 g, 16.7 mmol, 2.47 mL) was added and the mixture was stirred at 0-20°C for 2 h, after completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20°C, and then diluted with EtOAc 10 mL and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (1.4 g, 33% yield) as a colorless gum. ¹ H NMR (400 MHz, DMSO-d6) δ=3.95 (s, 2H), 3.26 (br s, 5H), 1.70-1.63 (m, 3H), 1.57 (br dd, J=4.0, 10.0 Hz, 4H), 1.41 (s, 9H), 1.38 (s, 9H), 1.29-1.22 (m, 5H).

Step 3-9-(2-hydroxyethoxy)-3-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

To a solution of tert-butyl 9-(2-(tert-butoxy)-2-oxoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (1.4 g, 3.7 mmol) in THF (15 mL) was added _LiAlH4 (207 mg, 5.48 mmol) at 0°C, and then the mixture was stirred at 0°C under _N2 atmosphere for 2 h. Upon completion, the reaction mixture was quenched with _H2O (0.01 mL) and 15% aqueous NaOH (0.1 mL) at 0°C. The mixture was then filtered and concentrated under reduced pressure to give the title compound (700 mg, 61% yield) as a colorless gum. ¹ HNMR (400MHz, DMSO-d6) δ = 4.51 (t, J = 5.2Hz, 1H), 3.49-3.46 (m, 1H), 3.48-3.37 (m, 3H), 3.29-3.22 (m, 5H), 1.67 (br dd, J = 4.0, 8.8Hz, 1H), 1.57 (br d, J = 10. 4Hz,3H),1.38(s,9H),1.36-1.32(m,4H),1.18-1.11(m,4H).

Step 4-tert-Butyl 9-(2-(Tosyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-(2-hydroxyethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (700 mg, 2.23 mmol) in DCM (10 mL) was added TEA (677 mg, 6.69 mmol) and 4-methylbenzenesulfonyl chloride (637 mg, 3.35 mmol) at 0°C, and then the mixture was stirred at 20°C for 12 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20°C, and then diluted with EtOAc (10 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 5/1) to give the title compound (430 mg, 29% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 7.78 (d, J = 8.4Hz, 2H), 7.48 (d, J = 8.0Hz, 2H), 4.11-4.08 (m, 2H), 3.55-3.51 (m, 2H), 3.29-3.21 (m, 5H), 2.42 (s, 3H), 1.63-1. 46(m,5H),1.38(s,9H),1.31-1.27(m,2H),1.25-1.21(m,3H),1.11-1.02(m,2H).

tert-Butyl 9-(2-aminoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (Intermediate FQ)

Step 1-9-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate Tert-butyl ester

A solution of tert-butyl 9-(2-(tosyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (200 mg, 428 μmol, intermediate FP) and potassium 1,3-dioxoisoindoline-2-chloride (119 mg, 642 μmol) in DMF (1 mL) was stirred at 50 °C for 2 h. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 20 °C, filtered and washed with H ₂ O (20 mL) to give the title compound (120 mg, 63% yield) as a white solid. LC-MS (ESI+) m/z 465.1 (M+Na) ⁺ .

Step 2-tert-Butyl 9-(2-aminoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 270 μmol) in EtOH (4 mL) was added NH ₂ NH ₂ .H ₂ O (102 mg, 2.04 mmol) and the mixture was then stirred at 50° C. for 2 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (130 mg) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 3.36-3.33 (m, 3H), 3.29-3.24 (m, 6H), 2.63 (t, J = 5.6Hz, 2H), 1.72-1.64 (m, 2H), 1.61-1.54 (m, 2H), 1.38 (s, 9H), 1.36-1.32 ( m,3H),1.28-1.23(m,3H),1.18-1.09(m,2H).

N-(2-(3-azaspiro[5.5]undec-9-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8-dihydropyridine)- (2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide (Intermediate FR)

Step 1-9-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl) tert-Butyl (amino)-3-methylphenylsulfonylamino)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of tert-butyl 9-(2-aminoethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 384 μmol, Intermediate FQ) and DIEA (397 mg, 3.07 mmol), 4A MS (100 mg, 384 μmol) in DCM (2 mL) was added 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (191 mg, 422 μmol, Intermediate CW), and then the mixture was stirred at 25° C. for 10 min. Upon completion, the reaction mixture was quenched with H ₂ O (2 mL) at 20° C. and extracted with DCM (2 mL×3). The combined organic layers were washed with brine (2 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give the title compound (300 mg) as a white solid. LC-MS (ESI+) m/z 729.2 (M+H) ⁺ .

Step 2-9-(2-(4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- tert-Butyl (3-methylphenylsulfonylamino)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate

To a solution of Pd/C (500 mg, 471 μmol, 10 wt%) in THF (3 mL) was added DIEA (106 mg, 822 μmol, 143 μL) and tert-butyl 9-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (300 mg, 411 μmol). The mixture was then stirred at 20 °C under _H atmosphere (15 PSI) for 2 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (120 mg) as a brown solid. LC-MS (ESI+) m/z 695.2 (M+H) ⁺ .

Step 3-N-(2-(3-azaspiro[5.5]undec-9-yloxy)ethyl)-4-((8-cyclopentyl-7-oxo-7,8- dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide

A solution of tert-butyl 9-(2-(4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (120 mg, 170 μmol) in DCM (5 mL) and HCl/dioxane (4 M, 1 mL) was stirred at 25° C. for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (100 mg) as a white solid. LC-MS (ESI+) m/z 595.2 (M+H) ⁺ .

3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- 1-(4-(2-amino-1-nitropropanal) (intermediate FS)

Step 1-3-[5-(3-hydroxyprop-1-enyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidin-2,6-dihydro- ketone

To a solution of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, intermediate J) and prop-2-en-1-ol (350 mg, 6.03 mmol) in dioxane (10.0 mL) was added P(t-Bu) ₃ (1.20 g, 591 μmol, 10 wt%), _Pd2 (dba) ₃ (270 mg, 295 μmol) and DIPEA (496 mg, 3.84 mmol). The mixture was stirred at 20 °C under _N2 for 16 h. Upon completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (750 mg, 80% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.74 (s, 1H), 11.08 (s, 1H), 9.80-9.62 (m, 1H), 7.11-7.07 (m, 1H), 7.01 (d, J = 8.0Hz, 1H), 6.95-6.93 (m, 1H), 6.96-6.83 (m, 1H ),5.41-5.25(m,1H),3.31(s,3H),2.94-2.89(m,2H),2.81-2.76(m,1H),2.75-2.65(m,1H),2.65-2.54(m,1H),2.04-1.94(m,1H).

Step 2-3-[5-(3-hydroxypropyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of 3-[5-[(E)-3-hydroxyprop-1-enyl]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (750 mg, 2.38 mmol) in THF (30.0 mL) was added PtO ₂ (54.0 mg, 237 μmol). The mixture was stirred at 20° C. under H ₂ (15 psi) for 16 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (0.1% FA) to give the title compound (220 mg, 29% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08(s,1H),7.06-6.96(m,2H),6.90-6.82(m,1H),5.38-5.27(m,1H),3.45-3.42(m,2H),3.33(s,3H),2.98-2.78(m,2H) ,2.76-2.68(m,1H),2.64-2.60(m,1H),2.59-2.52(m,1H),2.05-1.93(m,1H),1.83-1.66(m,2H).

Step 3-3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]propanal

To a solution of 3-[5-(3-hydroxypropyl)-3-methyl-2-oxo-benzoimidazol-1-yl] _{piperidine-2,6-dione (220 mg, 693 μmol) in DCM (10.0 mL) was added DMP (352 mg, 831 μmol). The mixture was stirred at 25 °C for 1 hour. Upon completion, the mixture was quenched with saturated Na2S2O3 (} 30 _mL ) and washed with saturated _NaHCO3 (2×30 mL). _The organic layer was dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (200 mg, 91% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 316.1 (M+H) ⁺ .

8-Cyclopentyl-2-((2-methyl-4-(piperazin-1-ylsulfonyl)phenyl)amino)pyrido[2,3-d]pyrimidine-7 (8H)-Ketone (Intermediate FT)

Step 1-4-((4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino tert-Butyl)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (90.3 mg, 485 μmol, CAS# 143238-38-4) in DCM (2 mL) was added DIEA (285 mg, 2.21 mmol) and Molecular sieves (200 mg) followed by 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (200 mg, 441 μmol, intermediate CW) were added and the mixture was stirred at 20° C. for 30 min. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (100 mg, 38% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 603.5 (M+H) ⁺ .

Step 2-4-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3- tert-Butyl (methylphenyl)sulfonyl)piperazine-1-carboxylate

To a solution of tert-butyl 4-((4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate (180 mg, 298 μmol) in THF (2 mL) was added TEA (90.6 mg, 895 μmol) and Pd/C (316 mg, 298 μmol). The mixture was stirred at 20 °C under _H2 atmosphere (15 PSI) for 4 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (100 mg, 59% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 569.3 (M+H) ⁺ .

Step 3-8-Cyclopentyl-2-((2-methyl-4-(piperazin-1-ylsulfonyl)phenyl)amino)pyrido[2,3-d] Pyrimidin-7(8H)-one

A solution of tert-butyl 4-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenyl)sulfonyl)piperazine-1-carboxylate (100 mg, 175 μmol) in HCl/dioxane (1 mL) was stirred at 20° C. for 20 min. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (70 mg) as an orange solid. LC-MS (ESI ⁺ ) m/z 469.2 (M+H) ⁺ .

6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5- 1-(4 ...nitrophenyl)-1-(4-nitrophenyl)-2-nitropropene)

Step 1-3-(5-(6-hydroxyhex-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole oxazol-1-yl)piperidin-2,6-dione

To a solution of hex-5-yn-1-ol (483 mg, 4.93 mmol) (CAS#928-90-5) and 3-(5-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (2 g, 5.91 mmol, Intermediate J) in ACN (10 mL) and THF (10 mL) was added XPhos Pd G3 (1.25 g, 1.48 mmol) and Cs ₂ CO ₃ (8.03 g, 24.6 mmol). The mixture was then stirred at 60 °C under N ₂ atmosphere for 12 h. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl (20 mL) at 0 °C and then diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were washed with sat. NaCl (20 mL x 3), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 5/1 to 0/1) to give the title compound (1.3 g, 74% yield) as an orange solid. LC-MS (ESI ⁺ ) m/z 356.2 (M+H) ⁺ .

Step 2-6-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole oxazol-5-yl)hex-5-ynaldehyde

To a solution of 3-(5-(6-hydroxyhex-1-yn-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (200 mg, 562 μmol) in DCM (2 mL) was added DMP (358 mg, 844 μmol) at 0°C. The mixture was stirred at 0-20°C for 12 hr. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25°C, and then diluted with Na ₂ SO ₃ (10 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with NaHCO ₃ (10 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The product was purified by flash silica gel chromatography ( 15g The residue was purified by Silica Flash Column, eluent 0 to 100% ethyl acetate/petroleum ether gradient at 20 mL/min) to give the title compound (80 mg, 40% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 354.2 (M+H) ⁺ .

(1S,3R)-3-(5-(1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxamido)-1- (tert-butyl )-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate (Intermediate FV)

To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylpyrrolidine-1-carboxylate (200 mg, 624.16 μmol, Intermediate CK) and 1-(3,6,9,12-tetraoxapentadeca-14-yn-1-yl)-1H-pyrazole-5-carboxylic acid (185.2 mg, 567.4 μmol, Intermediate CI) in ACN (5 mL) were added DIEA (734 mg, 5.67 mmol) and T ₃ P (1.7 g, 2.6 mmol, 50% solution), and the mixture was stirred at 80 °C for 41 h. After completion, the reaction mixture was quenched with H ₂ O (5 mL) and extracted with EtOAc (7 mL×2). The combined organic layers were washed with brine (5 mL×3), dried over Na ₂ SO ₄ and evaporated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (200 mg, 56% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 7.58 (d, J=2 Hz, 1H), 7.01 (s, 1H), 6.00 (s, 1H), 5.05-4.97 (m, 1H), 4.66 (t, J=5.6 Hz, 2H), 4.12 (d, J=2.4 Hz, 2H), 3.73 (t, J=5.6 Hz, 2H), 3.54-3.50 (m, 4H), 3.47-3.46 (m, 3H), 3.45 (s, 4H), 3.40 (t, J=2.4 Hz, 1H), 3.22 (br t,J＝6.4Hz,5H),3.07-3.01(m,1H),2.39-2.32(m,1H),1.90-1.84(m,1H),1.81-1.69(m,8H),1.51(s,9H).

3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H-benzo [d]Imidazol-1-yl)piperidine-2,6-dione (Intermediate FW)

Step 1-4-prop-2-ynyloxypiperidine-1-carboxylic acid tert-butyl ester

The solution of tert-butyl 4-hydroxypiperidine-1-formate (2.00g, 9.94mmol, CAS#109384-19-2) in anhydrous THF (10mL) was cooled to 0°C, and NaH (477mg, 11.9mmol, 60% oil dispersion) was added afterwards. The reaction mixture was stirred at 0°C for 0.5hr. Subsequently, 3-bromoprop-1-yne (1.18g, 9.94mmol, 856μL) was added. The resulting reaction mixture was stirred at 25°C for 12hr. After completion, the reaction mixture was quenched with water (1mL) and then diluted with ethyl acetate (100mL). The organic layer was washed with brine (20mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to obtain the title compound (2.38g, 100% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.22 (d, J = 2.4Hz, 2H), 3.84-3.75 (m, 2H), 3.73-3.70 (m, 1H), 3.15-3.09 (m, 2H), 2.43 (t, J = 2.4Hz, 1H), 1.93-1.82 (m, 2H), 1.61 -1.50(m,2H),1.47(s,9H).

Step 2-4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]propane-2- [Alkynyloxy]piperidine-1-carboxylic acid tert-butyl ester

3-(4-Bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (300 mg, 887 μmol, intermediate H), tert-butyl 4-prop-2-ynyloxypiperidine-1-carboxylate (318 mg, 1.33 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (124 mg, 177 μmol), CuI (33.8 mg, 177 μmol), A suspension of molecular sieves (400 mg) and Cs ₂ CO ₃ (1.16 g, 3.55 mmol) in DMF (5 mL) was degassed in vacuo and purged with N ₂ several times and then heated to 80 ° C for 2 hours under N _2. After completion, the reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with EA (50 mL) and water (20 mL). Afterwards, the organic layer was separated and washed with brine (5 mL×2), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase to give the title compound (222 mg, 48% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ )δ8.09(s,1H),7.10(d,J＝8.0Hz,1H),6.92(t,J＝8.0Hz,1H),6.69(d,J＝8.0Hz,1H),5.13(dd,J＝5.2,12.8Hz,1H),4.39(s,2H),3.76-3.66(m,6H),3.09- 3.03(m,2H),2.94-2.84(m,1H),2.82-2.71(m,1H),2.71-2.59(m,1H),2.22-2.11(m,1H),1.83-1.78(m,2H),1.57-1.49(m,2H),1.39(s,9H),LC-MS( ESI ⁺ )m/z441.2(M+H-56) ⁺ .

Step 3-3-[3-methyl-2-oxo-4-[3-(4-piperidinyloxy)prop-1-ynyl]benzimidazol-1-yl]piperidinyl Pyridine-2,6-dione

To a mixture of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]prop-2-ynyloxy]piperidine-1-carboxylate (1.50 g, 3.02 mmol) in DCM (30 mL) was added TFA (23.1 g, 202 mmol, 15 mL). The reaction mixture was stirred at 20 ° C for 1 hr. After completion, the reaction mixture was concentrated in vacuo to give the title compound (1.50 g, 97% yield, TFA salt) as a yellow oil. LC-MS (ESI+) m/z 397.2 (M+H) ⁺ .

3-(3-methyl-2-oxo-4-(piperazin-1-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6- Diketone (Intermediate FY)

Step 1-4-(3-methoxycarbonyl-2-nitro-phenyl)piperazine-1-carboxylic acid tert-butyl ester

To a solution of 3-fluoro-2-nitro-benzoate (10.0 g, 50.2 mmol, CAS#1214353-57-7) and tert-butylpiperazine-1-carboxylic acid methyl ester (11.2 g, 60.3 mmol, CAS#143238-38-4) in ACN (100 mL) was added DIPEA (19.5 g, 151 mmol). The reaction mixture was stirred at 50 °C for 12 hr. Upon completion, the mixture was concentrated in vacuo. The residue was dissolved in water (200 mL) and then extracted with EA (2 x 200 mL). The organic layer was washed with brine (2 x 100 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give the title compound (18.3 g, 100% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.86 (dd, J＝1.2, 8.0Hz, 1H), 7.82-7.79 (m, 1H), 7.74-7.68 (m, 1H), 3.83 (s, 3H), 3.40-3.35 (m, 4H), 2.88-2.84 (m, 4H), 1.41 (s, 9H).

Step 2-4-(2-amino-3-methoxycarbonyl-phenyl)piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(3-methoxycarbonyl-2-nitro-phenyl)piperazine-1-carboxylate (17.0 g, 46.5 mmol) in THF (15 mL) was added Pd/C (2.00 g, 10 wt%). The reaction mixture was stirred at 20 °C under _H2 atmosphere (15 Psi) for 12 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (15.2 g, 97% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.67(dd,J＝1.2,8.0Hz,1H),7.10(dd,J＝1.2,7.6Hz,1H),6.61(t,J＝7.6Hz,1H),6.24(br s,2H),4.28-3.95(m,2H),3.87(s,3H),3.16 -2.84(m,4H),2.80-2.55(m,2H),1.49(s,9H).

Step 3-4-[3-methoxycarbonyl-2-(methylamino)phenyl]piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(2-amino-3-methoxycarbonyl-phenyl)piperazine-1-carboxylate (15.0 g, 44.7 mmol) in 1,1,1,3,3,3-hexafluoropropan-2-ol (40 mL) was added methyl trifluoromethanesulfonate (9.54 g, 58.1 mmol) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hr. Upon completion, the mixture was diluted with water (200 mL) and then extracted with EA (2 x 200 mL). The organic layer was washed with brine (2 x 200 mL), dried _{over Na2SO4} , filtered and the filtrate concentrated in vacuo to give the title compound (15.0 g, 96% yield) as a yellow solid. ² .87(s,3H),2.80-2.74(m,4H),1.42(s _, 9H).

Step 4-3-(4-tert-Butyloxycarbonylpiperazin-1-yl)-2-(methylamino)benzoic acid

To a solution of tert-butyl 4-[3-methoxycarbonyl-2-(methylamino)phenyl]piperazine-1-carboxylate (14.0 g, 40.1 mmol) in a mixed solvent of H ₂ O (20 mL) and MeOH (140 mL) was added NaOH (4.81 g, 120 mmol). The reaction mixture was stirred at 70 °C for 12 hr. After completion, the mixture was concentrated in vacuo. The residue was diluted with water (200 mL) and extracted with EA (100 mL). The organic layer was discarded. The aqueous phase was acidified to pH=3-5 with HCl (1 N) and extracted with EA (2×100 mL). The organic layer was washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was triturated with MeOH/H ₂ O (1:10, 100 mL) and filtered. The filter cake was dried in vacuo to afford the title compound (9.60 g, 71% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 336.1 (M+H) ⁺ .

Step 5-tert-Butyl 4-(3-methyl-2-oxo-1H-benzimidazol-4-yl)piperazine-1-carboxylate

To a solution of 3-(4-tert-butoxycarbonylpiperazin-1-yl)-2-(methylamino)benzoic acid (9.60 g, 28.6 mmol) and DIPEA (11.1 g, 85.9 mmol) in t-BuOH (200 mL) was added DPPA (7.88 g, 28.6 mmol). The reaction mixture was stirred at 85 °C for 12 hr. Upon completion, the mixture was concentrated in vacuo. The residue was diluted with water (200 mL) and extracted with EA (2 x 200 mL). The organic layer was washed with brine (200 mL) and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (3.35 g, 35% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.84 (s, 1H), 6.94-6.87 (m, 1H), 6.85-6.79 (m, 1H), 6.75 (dd, J = 1.2, 7.6Hz, 1H), 4.06-3.80 (m, 2H), 3.55 (s, 3H), 3.20-2.87 (m,4H),2.76-2.56(m,2H),1.42(s,9H).

Step 6-4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo [4-(2-Benzimidazol-4-yl)piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(3-methyl-2-oxo-1H-benzimidazol-4-yl)piperazine-1-carboxylate (3.30 g, 9.93 mmol) in THF (50 mL) was added t-BuOK (1.67 g, 14.9 mmol) at 0°C. After 1 hr, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (4.54 g, 11.9 mmol, intermediate G) in THF (20 mL) was added. The reaction mixture was stirred at 0°C for 3 hr. Upon completion, the mixture was acidified to pH = 3-5 with FA, diluted with water (300 mL), and then extracted with EA (2 x 300 mL). The organic layer was washed with brine (200 mL) and concentrated in vacuo. The residue was purified by reverse phase flash (0.1% FA condition) to give the title compound (3.90 g, 70% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 564.3 (M+H) ⁺ .

Step 7-3-(3-methyl-2-oxo-4-piperazin-1-yl-benzoimidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 4-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]piperazine-1-carboxylate (3.90 g, 6.92 mmol) in TFA (40 mL) was added TfOH (5 mL). The reaction mixture was stirred at 65 ° C for 12 hr. After completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase rapid (0.1% FA conditions) to give the title compound (1.70 g, 63% yield, FA salt) as a blue solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.09 (s, 1H), 7.06-6.99 (m, 1H), 6.96-6.92 (m, 2H), 5.36 (dd, J = 5.2, 12.4Hz, 1H), 3.63 (s, 3H), 3.35-3.25 (m, 4H), 3.16-2.9 7(m,4H),2.91-2.82(m,1H),2.76-2.57(m,2H),2.05-1.93(m,1H).

1-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene (4-(2-(2-(2-(4-piperidine-1-yl)sulfonyl)piperidine-4-carboxaldehyde (Intermediate FZ)

Step 1-6-Chloro-8-cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amine 1-(2-(4-(2-yl)pyrido[2,3-d]pyrimidin-7(8H)-one

To a solution of 4-piperidinylmethanol (530 mg, 4.61 mmol, CAS# 6457-49-4) in DCM (20 mL) were added DIEA (2.71 g, 20.9 mmol, 3.65 mL), Molecular sieves (2 g) and 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (1.9 g, 4.19 mmol, intermediate CW). The mixture was stirred at 20 °C for 30 min. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 40g The residue was purified by HPLC-MS/MS (ESI ^{+) (HPLC-MS/MS) (Delta-HPLC, eluent 0 to 100% ethyl acetate/petroleum ether gradient at 100 mL/min) to give the title compound as a white solid (2 g, 90% yield). LC-MS (ESI+} ) m/z 532.1 (M+H) ⁺ .

Step 2-8-Cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrrolidone Irido[2,3-d]pyrimidin-7(8H)-one

To a solution of 6-chloro-8-cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 200 μmol) in THF (20 mL) was added TEA (57.0 mg, 563 μmol) and Pd/C (1 g, 943 μmol, 10 wt). The mixture was then stirred at 20 °C under _H atmosphere for 4 h. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give the title compound (50 mg, 54% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 498.2 (M+H) ⁺ .

Step 3-1-((4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3- (Methylphenyl)sulfonyl)piperidine-4-carboxaldehyde

To a solution of 8-cyclopentyl-2-((4-((4-(hydroxymethyl)piperidin-1-yl)sulfonyl)-2-methylphenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 1.00 mmol) in DCE (5 mL) was added DMP (639 mg, 1.51 mmol, 466 μL) at 0°C. The mixture was then stirred at 0-25°C for 2 h. Upon completion, the reaction mixture was washed _{with Na2SO3} (2 mL x 2) at 25°C, and then diluted with _NaHCO3 (2 mL) and extracted with EtOAc (2 mL x 2). The combined organic layers were washed with sat.NaCl (2 mL x 2), dried _{over Na2SO4} , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography 40g The residue was purified by HPLC-MS/MS (ESI+) (HPLC-MS/MS) (ESI+) (gradient 0 to 100% ethyl acetate/petroleum ether, 50 mL/min, eluent) to give the title compound as a white solid. LC-MS (ESI ⁺ ) m/z 496.3 (M+H) ⁺ .

3-(3-methyl-2-oxo-4-(piperazin-1-ylmethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin- 2,6-Diketone (intermediate GA)

Step 1 -4-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl] Piperazine-1-carboxylic acid tert-butyl ester

To a solution of 3-[4-(chloromethyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (400 mg, 1.30 mmol, intermediate FH) and tert-butyl piperazine-1-carboxylate (200 mg, 1.07 mmol, CAS# 143238-38-4) in ACN (5.00 mL) was added K ₂ CO ₃ (297 mg, 2.15 mmol). The mixture was stirred at 80° C. for 3 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (430 mg, 87% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.57(s,1H),7.02-6.95(m,1H),6.95-6.89(m,1H),6.81-6.75(m,1H),5.27(dd,J=5.2,12.4Hz,1H),3.80(s,3H),3.75-3.67(m,2 H),3.47-3.35(m,4H),2.99-2.90(m,1H),2.90-2.80(m,1H),2.80-2.68(m,1H),2.55-2.35(m,4H),2.29-2.17(m,1H),1.46(s,9H).

Step 2-3-[3-methyl-2-oxo-4-(piperazin-1-ylmethyl)benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]methyl]piperazine-1-carboxylate (60.0 mg, 131 μmol) in DCM (5.00 mL) was added HCl/dioxane (4 M, 1.00 mL). The reaction mixture was stirred at 20 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (50.0 mg, 96% yield, HCl salt) as a white solid. LC-MS (ESI ⁺ ) m/z 358.1 (M+H) ⁺ .

2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)ethyl 4-methylbenzenesulfonate Ester (Intermediate GB)

Step 1-tert-Butyl 2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)acetate ester

To a solution of tert- _butyl 2-(((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)oxy)acetate (3.50 g, 9.63 mmol, CAS# 27489-63-0) in DMF (40 mL) under N2 at 0°C was added NaH (578 mg, 14.5 mmol, 60% dispersion in mineral oil) and the mixture was stirred for 0.5 h. Then _CH3I (2.73 g, 19.3 mmol) was added and the reaction mixture was stirred at 0°C for 2 h. Upon completion, the reaction was quenched with sat. _{NH4Cl (} 50 mL) and then extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine (50 mL x 4), dried over _Na2SO4 and evaporated. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 9/1) to give the title compound (2.40 g, 66% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.41-7.28 (m, 5H), 5.14 (s, 2H), 3.99 (d, J=1.6 Hz, 2H), 3.33-3.23 (m, 1H), 2.79 (s, 3H), 2.14 (d, J=10.8 Hz, 2H), 1.76 (d, J=10.4 Hz, 2H), 1.49 (d, J=1.6 Hz, 13H).

Step 2-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)(methyl)carbamic acid benzyl ester

To a solution of tert-butyl 2-(((lr,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)acetate (2.40 g, 6.36 mmol) in THF (30 mL) under _N2 at 0°C was added LAH (362 mg, 9.54 mmol) and the mixture was stirred at 0°C for 2 h. Upon completion, the reaction was quenched by addition of _H2O (2.16 mL), filtered and evaporated to give the title compound as a colorless oil (1.60 g). ¹ H NMR (400MHz, DMSO-d6) δ＝7.37-7.34(m,3H),7.33-7.32(m,1H),7.27-7.19(m,1H),5.15(t,J＝5.6Hz,1H),5.07(s,2H),4.55-4.47(m,4H),3.82(d,J＝ 5.2Hz,1H),3.16-3.13(m,1H),2.73(s,3H),1.99(d,J＝2.8Hz,2H),1.78-1.73(m,2H),1.56(d,J＝8.0Hz,2H),1.14(d,J＝10.8Hz,2H).

Step 3-2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy ethyl ester

To a solution of benzyl ((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)(methyl)carbamate (1.60 g, 5.21 mmol) in DCM (16 mL) under _N2 at 0°C were added TEA (1.05 g, 10.4 mmol), DMAP (159 mg, 1.30 mmol) and TosCl (1.19 g, 6.25 mmol), and the mixture was stirred at 20°C for 2 h. After completion, the reaction mixture was diluted with water (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (8 mL x 3), dried over _Na2SO4 and evaporated. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = _5/1 to 4/1) to give the title compound (800 mg, 33% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d6) δ = 7.81-7.75 (m, 2H), 7.48 (d, J = 8.0Hz, 2H), 7.41-7.29 (m, 5H), 5.06 (s, 2H), 4.11-4.07 (m, 2H), 3.85-3.72 (m, 1H), 3.57-3.53 (m,2H),3.15-3.06(m,1H),2.74-2.69(m,3H),2.41(s,3H),1.89(d,J＝13.2Hz,2H),1.57-1.44(m,4H),1.09(d,J＝12.4Hz,2H).

((1r,4r)-4-(2-aminoethoxy)cyclohexyl)(methyl)carbamic acid benzyl ester (intermediate GC)

Step 1-((1r,4r)-4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)cyclohexyl)(methyl)amino Benzyl formate

A solution of 2-(((1r,4r)-4-(((benzyloxy)carbonyl)(methyl)amino)cyclohexyl)oxy)ethyl 4-methylbenzenesulfonate (800 mg, 2 mmol, Intermediate GB) and 1,3-dioxoisoindoline-2-potassium chloride (482 mg, 2.60 mmol) in DMF (8 mL) was stirred at 50 °C for 3 h. Upon completion, the mixture was poured into _H2O (5 mL) and filtered. The filter cake was concentrated in vacuo to give the title compound (680 mg, 90% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 7.90-7.81 (m, 4H), 7.40-7.26 (m, 5H), 5.05 (s, 2H), 3.84-3.74 (m, 1H), 3.73-3.68 (m, 2H), 3.64-3.58 (m, 2H), 3.26-3.16 (m ,1H),2.70(s,3H),1.92(d,J＝12.8Hz,2H),1.58-1.47(m,4H),1.12(dd,J＝5.2,11.2Hz,2H).

Step 2-((1r,4r)-4-(2-aminoethoxy)cyclohexyl)(methyl)carbamic acid benzyl ester

To a solution of benzyl ((lr,4r)-4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)cyclohexyl)(methyl)carbamate (680 mg, 1.56 mmol) in EtOH (14 mL) was added _N2H4.H2O (398 mg, 7.79 mmol). The _mixture was stirred at 50°C for 2 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (470 _mg ) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ )δ=7.43-7.28(m,5H),5.07(s,2H),3.88-3.77(m,1H),3.47-3.41(m,2H),3.19-3.13(m,1H),2.73(s,3H),2.67-2.62(m,2H) ,2.05-1.97(m,2H),1.56(d,J=8.0Hz,3H),1.25-1.12(m,3H).

4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methyl-N-(2- (((1r,4r)-4-(Methylamino)cyclohexyl)oxy)ethyl)benzenesulfonamide (Intermediate GD)

Step 1-((1r,4r)-4-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (2-pyridin-2-yl)amino)-3-methylphenylsulfonylamino)ethoxy)cyclohexyl)(methyl)carbamic acid benzyl ester

To a solution of benzyl ((1r,4r)-4-(2-aminoethoxy)cyclohexyl)(methyl)carbamate (446 mg, 1.46 mmol, intermediate GC) in DCM (6 mL) were added DIEA (855 mg, 6.62 mmol), Molecular sieves (600 mg) and 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzene-1-sulfonyl chloride (600 mg, 1.32 mmol, intermediate CW). The mixture was stirred at 25 °C for 1 h. After completion, the mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1 to 1/2) to give the title compound (900 mg, 94% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ=9.68(s,1H),8.76(s,1H),8.18(s,1H),7.74-7.68(m,2H),7.65-7.60(m,2H),7.40-7.30(m,5H),5.76(s,1H),5.06(s,2H),3.86-3.73(m,1H), 3.39(t,J＝6.0Hz,2H) ,3.17-3.04(m,1H),2.89(q,J＝6.0Hz,2H),2.70(s,3H),2.33(s,3H),2.14-2.09(m,2H),1.97-1.92(m,2H),1.76-1.64(m,5H),1.56-1.46(m,5H), 1.13(d,J=3.6Hz,2H).

Step 2-4-((8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methyl N-(2-(((1r,4r)-4-(methylamino)cyclohexyl)oxy)ethyl)benzenesulfonamide

To a solution _{of benzyl} ((lr,4r)-4-(2-(4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylphenylsulfonamido)ethoxy)cyclohexyl)(methyl)carbamate (300 mg, 0.415 mmol) and DIEA (161 mg, 1.24 mmol) in EtOH (3 mL) under N2 was added Pd/C (150 mg, 10 wt%). The suspension was degassed in vacuo and purged with _H2 several times. The mixture was stirred under _H2 (15 psi) at 25 °C for 2 h. Additional Pd/C (300 mg, 10 wt%) was then added and the mixture was stirred under _H2 (15 psi) at 25 °C for 12 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (230 mg) as a yellow oil. LC-MS(ESI ⁺ )m/z 555.3(M+H) ⁺ .

tert-Butyl 3-(2-(Tosyloxy)ethoxy)azetidine-1-carboxylate (Intermediate GE)

Step 1-tert-Butyl 3-(2-(tert-butoxy)-2-oxoethoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10 g, 57.7 mmol, CAS# 141699-55-0) in DMF (100 mL) was added NaH (2.77 g, 69.2 mmol, 60% dispersion in mineral oil) at 0°C. The mixture was stirred at 25°C for 1 h and then tert-butyl 2-bromoacetate (16.9 g, 86.6 mmol) was added and the mixture was stirred at 40°C for 2 h. Upon completion, the reaction mixture was quenched with _NH4Cl (100 mL) and extracted with EtOAC (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried _{over Na2SO4} and evaporated. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (11 g, 66% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 4.32 (tt, J = 4.4, 6.4Hz, 1H), 4.08 (dd, J = 6.4, 10.0Hz, 2H), 3.94-3.89 (m, 4H), 1.47 (s, 9H), 1.43 (s, 9H).

Step 2-tert-Butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-(2-(tert-butoxy)-2-oxoethoxy)azetidine-1-carboxylate (8.8 g, 31 mmol) in THF (90 mL) was added LAH (1.74 g, 45.9 mmol) at 0° C., and the mixture was stirred at 0° C. for 2 h. Upon completion, the mixture was quenched with H ₂ O (1.8 mL) and 15% aqueous NaOH (1.8 mL), more H ₂ O (6 mL), and the mixture was stirred at 0° C. for 10 min. The mixture was then filtered and the filtrate was concentrated to give the title compound (4.4 g) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ = 4.27-4.16 (m, 1H), 4.16-3.94 (m, 4H), 3.83-3.74 (m, 2H), 3.71-3.64 (m, 4H), 3.58-3.51 (m, 3H), 3.41 (td, J = 4.4, 9.2Hz, 5H), 3.00-2.88(m,2H),2.29(s,3H),1.37(s,9H).

Step 3-tert-Butyl 3-(2-(tosyloxy)ethoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-(2-hydroxyethoxy)azetidine-1-carboxylate (4.4 g, 20.3 mmol) in DCM (80 mL) and THF (20 mL) was added TEA (4.10 g, 40.5 mmol), DMAP (618 mg, 5.06 mmol) and 4-methylbenzenesulfonyl chloride (5.79 g, 30.4 mmol), then the mixture was stirred at 25 °C for 12 h. After completion, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried _{over Na2SO4} , and concentrated in vacuo. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 48%-78%, 15 min) to give the title compound (2.1 g, 28% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.85-7.79 (m, 2H), 7.39-7.34 (m, 3H), 4.21-4.15 (m, 3H), 4.05-3.98 (m, 2H), 3.76-3.70 (m, 2H), 3.62-3.56 (m, 2H), 2.47 (s, 4H), 1.45 (s, 10H).

3-(5-(1-(2-(azetidin-3-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo-2,3-diol H-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate GF)

Step 1-3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo [d] tert-butyl imidazol-5-yl)piperidin-1-yl)ethoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-(2-(tosyloxy)ethoxy)azetidine-1-carboxylate (250 mg, 673 μmol, Intermediate GE) in DMF (2 mL) was added 3-(3-methyl-2-oxo-5-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (192 mg, 560 μmol, Intermediate DB using SMA) and DIEA (217.5 mg, 1.68 mmol, 293.08 μL), then the mixture was stirred at 60 °C for 12 hr. Upon completion, the reaction mixture was quenched with _NH4Cl (5 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (7 mL _x 3), dried over _Na2SO4 and evaporated. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (40 mg, 13% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 542.3 (M+H) ⁺ .

Step 2-3-(5-(1-(2-(azetidin-3-yloxy)ethyl)piperidin-4-yl)-3-methyl-2-oxo- 2,3-Dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 3-(2-(4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidin-1-yl)ethoxy)azetidine-1-carboxylate (40 mg, 73.9 μmol) in DCM (2 mL) was added TFA (0.4 mL) and the mixture was then stirred at 25 °C for 4 h. Upon completion, the mixture was filtered and concentrated. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (60 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 442.2 (M+H) ⁺ .

(Intermediate GG)

Tert-butyl ((1r,4r)-4-(2-(prop-2-yn-1-yloxy)ethoxy)cyclohexyl)carbamate (intermediate GH)

Step 1-ethyl 2-(((1r,4r)-4-((tert-butyloxycarbonyl)amino)cyclohexyl)oxy)acetate

To a solution of tert-butyl N-(4-hydroxycyclohexyl)carbamate (12 g, 56 mmol, CAS#111300-06-2) in DCM (100 mL) was added diacetoxyrhodium (1.23 g, 5.57 mmol) and ethyl 2-diazoacetate (47.7 g, 334 mmol) at 0 ° C under a stream of nitrogen. The reactants were then stirred at 20 ° C under a nitrogen atmosphere for 5 h. After completion, the reactants were poured into water (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (2×80 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate = 100: 1 to 100: 20) to give the title compound (11 g, 65% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 4.43-4.31 (m, 1H), 3.74-3.68 (m, 2H), 3.59-3.54 (m, 2H), 3.51-3.37 (m, 1H), 3.27 (qt, J = 3.6, 10.8Hz, 1H), 2.02 (br s, 4H), 1.44 (s,9H),1.41-1.33(m,2H),1.21-1.11(m,2H).

Step 2-((1r,4r)-4-(2-hydroxyethoxy)cyclohexyl)carbamic acid tert-butyl ester

To a solution of ethyl 2-[4-(tert-butoxycarbonylamino)cyclohexyloxy]acetate (11 g, 37 mmol) in THF (110 mL) and MeOH (22 mL) was added LiBH ₄ (2.87 g, 131 mmol) at 0° C. under a stream of nitrogen. The reactant was then stirred at 20° C. under a nitrogen atmosphere for 2 h. Upon completion, the reactant was quenched with saturated aqueous citric acid solution (120 mL) and extracted with ethyl acetate (100 mL×2). The combined organic phases were washed with brine (60 mL×2) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (6.5 g, 69% yield) as a yellow gum. ¹ H NMR (400MHz, CDCl ₃ ) δ = 4.46-4.27 (m, 1H), 3.73-3.67 (m, 2H), 3.61-3.53 (m, 2H), 3.50-3.37 (m, 1H), 3.33-3.19 (m, 1H), 2.04 (br dd, J = 2.1, 10.5Hz, 4H), 1.50-1.42(m,9H),1.41-1.33(m,2H),1.21-1.08(m,2H).

Step 3-tert-Butyl ((1r, 4r)-4-(2-(prop-2-yn-1-yloxy)ethoxy)cyclohexyl)carbamate

To a solution of tert-butyl N-[4-(2-hydroxyethoxy)cyclohexyl]carbamate (0.4 g, 2 mmol) in THF (10 mL) was added NaH (123 mg, 3.08 mmol, 60% dispersion in mineral oil) and 3-bromoprop-1-yne (366 mg, 3.08 mmol) at 0 ° C under a nitrogen stream. The reactants were then stirred at 20 ° C under a nitrogen atmosphere for 10 h. After completion, the reactants were poured into a saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phases were washed with brine (2×10 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:20) to give the title compound (450 mg, 98% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 4.48-4.28 (m, 1H), 4.21 (d, J = 2.4Hz, 2H), 3.73-3.58 (m, 4H), 3.51-3.35 (m, 1H), 3.25 (tt, J = 3.6, 10.4Hz, 1H), 2.42 (t, J = 2.4Hz ,1H),2.08-1.96(m,4H),1.49-1.41(m,8H),1.40-1.32(m,2H),1.20-1.05(m,2H).

3-(5-((Z)-4-(2-(((1r,4r)-4-aminocyclohexyl)oxy)ethoxy)-2-chlorobut-1-en-1-yl)- 3-Methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate GI)

Step 1-((1r,4r)-4-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dioxopiperidin-3-yl)- tert-Butyl (1H-benzo[d]imidazol-5-yl)prop-2-yn-1-yl)oxy)ethoxy)cyclohexyl)carbamate

To a solution of tert-butyl N-[4-(2-prop-2-ynyloxyethoxy)cyclohexyl]carbamate (0.45 g, 1.51 mmol, intermediate GH) and 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (562 mg, 1.66 mmol, intermediate J) in THF (4.5 mL) and ACN (4.5 mL) was added Cs ₂ CO ₃ (2.47 g, 7.57 mmol) and XPhos Pd G3 (384 mg, 453 μmol) at 20° C. under a stream of nitrogen. The reaction was then stirred at 60° C. under a nitrogen atmosphere for 10 h. Upon completion, the reaction was poured into water (10 mL) and extracted with ethyl acetate (15 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over sodium sulfate. Then filtered to obtain the filtrate and concentrated to obtain a residue. The residue was purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate=100:1 to 100:80). The title compound (550 mg, 65.5% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ=7.11 (dd, J=1.2, 8.2 Hz, 1H), 7.04 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 5.13 (dd, J=5.2, 12.8 Hz, 1H), 4.42-4.25 (m, 3H), 3.70-3.64 (m, 2H), 3.63-3.57 (m, 2H), 3.35 (s, 4H 1 .11-0.97(m,2H).

Step 2-3-(5-((Z)-4-(2-(((1r,4r)-4-aminocyclohexyl)oxy)ethoxy)-2-chlorobut-1-ene- 1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione

A solution of tert-butyl N-[4-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]prop-2-ynyloxy]ethoxy]cyclohexyl]carbamate (400 mg, 721 μmol) in HCl/dioxane (4M, 5 mL) at 0°C under a stream of nitrogen. The reaction was then stirred at 20°C under a nitrogen atmosphere for 2 h. Upon completion, the reaction was concentrated to give the title compound (400 mg) as a yellow solid. LC-MS (ESI ⁺ ) m/z 491.2 (M+H) ⁺ .

2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethylamine (intermediate GJ)

Step 1-(1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexanol

To a solution of 4-(hydroxymethyl)cyclohexanol (10 g, 76.8 mmol, CAS# 3685-27-6) and imidazole (5.75 g, 84.5 mmol) in DMF (300 mL) was added TBDPSCl (22.1 g, 80.6 mmol) at 0°C, and then the mixture was stirred at 25°C for 12 h. After completion, the mixture was quenched with water (300 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL x 3) and dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (19 g, 67% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.71-7.63 (m, 4H), 7.48-7.35 (m, 6H), 3.56 (tt, J = 4.4, 10.8Hz, 1H), 3.47 (d, J = 6.4Hz, 2H), 2.05-1.96 (m, 2H), 1.90-1.79 (m, 2 H),1.33-1.20(m,3H),1.06(m,11H).

Step 2-2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)acetic acid Ethyl ester

To a solution of (1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexanol (10 g, 30 mmol) and _Rh2 (OAc) ₄ (1.20 g, 2.71 mmol) in DCM (100 mL) was added ethyl 2-diazoacetate (18.5 g, 162 mmol) dropwise at 0°C, and then the mixture was stirred at 25°C under _N2 atmosphere for 12 h. After completion, the mixture was quenched with HOAc (50 mL) and _H2O (100 mL), and then extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL x ₃ ) and dried over _Na2SO4 , and concentrated in vacuo and purified by silica gel chromatography (petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (8 g, 65% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.71-7.61 (m, 4H), 7.44-7.34 (m, 6H), 4.31-4.23 (m, 1H), 4.23 (br d, J = 7.2Hz, 2H), 4.12 (s, 2H), 3.46 (d, J = 6.1Hz, 2H), 3.35-3.2 1(m,1H),2.18-2.02(m,2H),1.92-1.79(m,2H),1.05(s,9H).

Step 3-2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethanol

To a solution of ethyl 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]acetate (6 g, 10 mmol) in THF (60 mL) and MeOH (12 mL) was added LiBH ₄ (862 mg, 39.5 mmol) at 0° C. The mixture was stirred at 0-20° C. for 2 h. Upon completion, the reaction mixture was quenched with the addition of saturated aqueous citric acid solution (120 mL) at 0° C., and then diluted with EtOAc (120 mL) and extracted with EtOAc (120 mL×3). The combined organic layers were washed with brine (120 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (5 g, 92% yield) as a white solid. LC-MS(ESI ⁺ )m/z 413.1(M+H) ⁺ .

Step 4-2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexanesulfonate 4-( ...2-nitrophenyl)oxy)ethyl ester

To a solution of 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethanol (5 g, 12.1 mmol) in DCM (80 mL) and THF (20 mL) was added TEA (2.45 g, 24.2 mmol), DMAP (370 mg, 3.03 mmol), and TosCl (3.47 g, 18.1 mmol). The mixture was stirred at 25 °C for 12 h. After completion, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3) and dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (4 g, 58% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.82 (d, J = 8.4Hz, 2H), 7.66 (dd, J = 1.2, 7.6Hz, 4H), 7.47-7.31 (m, 8H), 4.22-4.13 (m, 2H), 3.69-3.64 (m, 2H), 3.46 (d, J = 6.0Hz, 2 H),3.22-3.08(m,1H),2.45(s,3H),1.96(br d,J＝9.6Hz,2H),1.87-1.77(m,2H),1.48(dt,J＝2.4,6.0Hz,1H),1.27(t,J＝7.2Hz,1H),1.21-1.10(m,2H),1.06(s,9H),1.02-0.85(m,3H).

Step 5 -2-(2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy) ethyl)isoindoline-1,3-dione

To a solution of 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl 4-methylbenzenesulfonate (2 g, 3.53 mmol) in DMF (10 mL) was added (1,3-dioxoisoindolin-2-yl)potassium (980 mg, 5.29 mmol), and the mixture was then stirred at 50 °C for 4 h. After completion, the mixture was quenched with water (10 mL) and filtered. The filter cake was washed with water (10 mL x 3) to give the title compound (2 g) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.88 (dd, J = 3.2, 5.2Hz, 2H), 7.74 (dd, J = 3.2, 5.2Hz, 2H), 7.66 (dd, J = 1.6, 7.6Hz, 4H), 7.48-7.32 (m, 6H), 3.95-3.86 (m, 2H), 3.79-3. 69(m,2H),3.45(d,J＝6.4Hz,2H),3.28-3.18(m,1H),2.05-1.95(m,2H),1. 88-1.79(m,2H),1.56-1.45(m,1H),1.26-1.13(m,2H),1.10-0.91(m,11H) .

Step 6-2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethylamine

To a solution of 2-[2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl]isoindoline-1,3-dione (2 g, 3.69 mmol) in EtOH (80 mL) was added _NH2NH2.H2O (1.63 g, _27.6 mmol, 85% solution), and the mixture was stirred at 50°C for 2 h. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound as a yellow gum (1.2 _g ). LC-MS (ESI ⁺ ) m/z 442.3 (M+K) ⁺ .

4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-N-(2- (((1r,4r)-4-Formylcyclohexyl)oxy)ethyl)-3-methylbenzenesulfonamide (Intermediate GK)

Step 1 - N-(2-(((1r,4r)-4-(((tert-butyldiphenylsilyl)oxy)methyl)cyclohexyl)oxy)ethyl 4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl Amide

To a solution of 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (500 mg, 1.10 mmol, intermediate CW) and 2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethanamine (681 mg, 1.65 mmol, intermediate GJ) in DCM (10 mL) was added DIEA (712 mg, 5.51 mmol) and Molecular sieves (500 mg) were added and the mixture was then stirred at 25°C for 30 min. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound as a yellow oil (900 mg). LC-MS (ESI ⁺ ) m/z 828.3 (M+H) ⁺ .

Step 2-4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- N-(2-(((1r,4r)-4-(hydroxymethyl)cyclohexyl)oxy)ethyl)-3-methylbenzenesulfonamide

A solution of N-[2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide (900 mg, 1.09 mmol) in TBAF (2M, 10 mL) was stirred at 25°C for 1 h. After completion, the mixture was concentrated in vacuo and purified by reverse phase HPLC (0.1% FA condition) to give the title compound (250 mg, 39% yield) as a yellow oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.57 (s, 1H), 8.33 (d, J=8.4 Hz, 1H), 7.79-7.74 (m, 3H), 7.42 (br s,1H),5.92(quintet,J＝8.8Hz,1H),4.85(t,J＝6.0Hz,1H),3.54(t,J＝5.2Hz,2H),3.46(d,J＝6.4Hz,2H),3.18-3.09(m,3H),2.45(s,3H),2.36-2.25(m,2H ),2.13-1.98(m,5H),1.96-1.78(m,5H),1.75-1.66(m,3H),1.50-1.40(m,2H),1.25-1.10(m,3H),1.04-0.90(m,2H).

Step 3-4-((6-chloro-8-cyclopentyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)- N-(2-(((1r,4r)-4-Formylcyclohexyl)oxy)ethyl)-3-methylbenzenesulfonamide

To a solution of 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-N-[2-[4-(hydroxymethyl)cyclohexyloxy]ethyl]-3-methyl-benzenesulfonamide (200 mg, 338 μmol) in DCM (4 mL) was added DMP (215 mg, 508 μmol), then the mixture was stirred at 25 °C for 12 h. Upon completion, the mixture was quenched with sat. NaHCO ₃ (10 mL) and extracted with EtOAc (10 mL×3), the combined organic layers were washed with brine (10 mL×3), dried over Na ₂ SO ₄ , and concentrated in vacuo to give the title compound (250 mg) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ )δ＝9.64(d,J＝1.2Hz,1H),8.58(s,1H),8.35(d,J＝8.4Hz,1H),8.27(dd,J＝1.6,7.6Hz,1H),8.06-8.00(m,1H),7.94(ddd,J＝1.6,7.2,8.4Hz,1H),7.78-7.74(m,4H),7.32(s,1H),5.93(quintet, J＝8.8Hz,1H),4.83(t,J＝6.0Hz,1H),3.54(t,J＝5.2Hz,2H),3.20-3.10(m,3H),2.45(s,3H),2.38-2.28(m,2H),2.09-1.98(m,7H),1.96-1.85(m,3H), 1.76-1.65(m,3H),1.42-1.22(m,5H).

3-[4-[4-[azetidin-3-ylmethyl(methyl)amino]-1-piperidinyl]-3-methyl-2-oxo-benzo [Imidazol-1-yl]piperidine-2,6-dione (Intermediate GL)

Step 1-3-[[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4- [piperidinyl]-methyl-amino]methyl]azetidine-1-carboxylic acid tert-butyl ester

To a mixture of 3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (100 mg, 245 μmol, HCl, intermediate EG) in a mixed solvent of THF (2 mL) and DMF (0.5 mL) was added DIEA (63.3 mg, 490 μmol) at -15°C until pH = 8. The mixture was then stirred at -15°C for 10 min, and HOAc (44.1 mg, 735 μmol) was added at -15°C until pH = 6. The mixture was then stirred at -15°C for 20 min. After that, tert-butyl 3-formylazetidine-1-carboxylate (47.6 mg, 257 μmol, CAS# 177947-96-5) was added and the mixture was stirred at -15°C for 1 hr. Finally, NaBH(OAc) ₃ (103 mg, 490 μmol) was added. The resulting reaction mixture was stirred at -15 °C for 1 hr. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex LunaC18 100*30mm*5μm; mobile phase: [water(FA)-ACN]; B%: 3%-33%, 8 min) to give the title compound (60 mg, 45% yield) as a white solid. ² .89(s,1H),2.71-2.67(m,2H),2.63(s,2H) _, 2.19(s,3H),2.02-1.96(m,1H ),1.82-1.74(m,2H),1.71-1.59(m,2H),1.37(s,9H),1.36(d,J＝1.2Hz,4H ). LCMS(ESI ⁺ )m/z541.2(M+H) ⁺ .

Step 2-3-[4-[4-[azetidin-3-ylmethyl(methyl)amino]-1-piperidinyl]-3-methyl-2-oxo [-Benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 3-[[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]-methyl-amino]methyl]azetidine-1-carboxylate (40.0 mg, 73.9 μmol) in DCM (2 mL) was added TFA (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated in vacuo to give the title compound (40.0 mg, 97% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 441.1 (M+H) ⁺ .

Tert-butyl N-(3-oxopropyl)carbamate (Intermediate GM)

To a solution of tert-butyl N-(3-hydroxypropyl)carbamate (500 mg, 2.85 mmol, CAS #58885-58-8) in DCM (6 mL) was added DMP ( _1.45 g, 3.42 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched _{with Na2S2O3} · _5H2O (10 mL) and extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=10/1 to 5/1) to give the title compound (300 mg, 60% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 9.82 (s, 1H), 4.91 (d, J = 0.8Hz, 1H), 3.43 (q, J = 5.6Hz, 2H), 2.72 (t, J = 5.6Hz, 2H), 1.44 (s, 9H).

3-[4-[4-[3-aminopropyl(methyl)amino]-1-piperidinyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidinyl Pyridine-2,6-dione (Intermediate GN)

Step 1-N-[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]- 4-Piperidinyl]-methyl-amino]propyl]carbamic acid tert-butyl ester 3109

To a solution of 3-[3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (100 mg, 269 μmol, HCl salt, intermediate EG) and tert-butyl N-(3-oxopropyl)carbamate (60.6 mg, 350 μmol, intermediate GM) in a mixed solution of THF (2 mL) and DMF (0.5 mL) was added KOAc (264 mg, 2.69 mmol) and NaBH(OAc) ₃ (114 mg, 538 μmol). The mixture was stirred at 0° C. for 1 hr. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) at 0° C. and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex lunaC18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 5%-35%, 9 min) to give the title compound (75.0 mg, 52% yield) as a white solid. LCMS (ESI ⁺ ) m/z 529.5 (M+H) ⁺ .

Step 2-3-[4-[4-[3-aminopropyl(methyl)amino]-1-piperidinyl]-3-methyl-2-oxo-benzimidazole- 1-yl]piperidin-2,6-dione

To a solution of tert-butyl N-[3-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]-methyl-amino]propyl]carbamate (75.0 mg, 141 μmol) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (75.0 mg, 97% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 429.0 (M+H) ⁺ .

1-[8-[4-(Methylamino)-1-piperidinyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione (Intermediate GO)

Step 1-4-Bromo-8-chloro-isoquinoline

A mixture of 8-chloroisoquinoline (5.00 g, 30.5 mmol, CAS #34784-07-1), NBS (7.07 g, 39.7 mmol) in HOAc (50 mL) was degassed and purged with N ₂ three times, and then the mixture was stirred at 50 ° C under N ₂ atmosphere for 40 minutes. After completion, the reaction mixture was neutralized with 15% NaOH (20 mL) and the mixture was extracted with EA (3×20 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography to give the title compound (400 mg, 73.90% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ -d) δ9.58 (s, 1H), 8.79 (s, 1H), 8.12-8.05 (m, 1H), 7.73-7.66 (m, 2H).

Step 2-1-(8-chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione

To a solution of 4-bromo-8-chloro-isoquinoline (200 mg, 824 μmol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (231 mg, 989 μmol, intermediate CS) in DMF (3 mL) was added CuI (47.1 mg, 247 μmol), K ₂ CO ₃ (227 mg, 1.65 mmol) and 2-aminoacetic acid (18.5 mg, 247 μmol). The mixture was then purged with N ₂ three times and stirred at 140 ° C for 8 hours. After completion, the mixture was filtered, diluted with water (100 mL) and extracted with EA (5×80 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by reverse phase HPLC (0.1% FA) to give the title compound (99.2 mg, 30.41% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.56 (s, 1H), 8.72 (s, 1H), 7.98 (d, J = 8.4Hz, 1H), 7.91-7.87 (m, 1H), 7.83-7.77 (m, 1H), 7.29-7.23 (m, 2H), 6.91-6.84 (m, 2H) ),4.84(s,2H),4.01-3.94(m,1H),3.80-3.75(m,1H),3.73-3.71(m,3H),3.20-3.12(m,1H),3.01-2.93(m,1H). LC-MS(ESI ⁺ )m/z 396.0(M+H) ⁺ .

Step 3 - N-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-8-iso [quinolinyl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester

To a solution of 1-(8-chloro-4-isoquinolyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (200 mg, 505 μmol) and tert-butyl N-methyl-N-(4-piperidinyl)carbamate (119 mg, 555 μmol, CAS# 108612-54-0) in dioxane (4 mL) was added Cs ₂ CO ₃ (329 mg, 1.01 mmol) and Pd-PEPPSI-I Hept ^Cl 3-chloropyridine (49.1 mg, 50.5 μmol), then the mixture was stirred at 80 °C for 8 hours. After completion, the mixture was filtered, diluted with water (20 mL) and extracted with EA (4×10 mL). The extract was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (216 mg, 74.52% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.45(s,1H),8.53(s,1H),7.72-7.66(m,1H),7.54(d,J＝8.4Hz,1H),7.31-7.24(m,3H),6.88(d,J＝8.8Hz,2H),4.83(s,2H),3.93-3.87(m,1H),3.7 8-3.71(m,4H),3.50-3.42(m,2H),3.17-3.08(m,1H),2.99-2.96(m,1H),2.81(s,3H),2.18-2.03(m,2H),1.75-1.68(m,2H),1.43(s,9H),0.88-0 .70(m,3H); LC-MS(ESI ⁺ )m/z 574.3(M+H) ⁺ .

Step 4-1-[8-[4-(Methylamino)-1-piperidinyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione

A solution of N-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]-8-isoquinolinyl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester (206 mg, 359 μmol) in TFA (0.5 mL) and TfOH (0.05 mL) was stirred at 70° C. for 1 hour. After completion, the mixture was concentrated in vacuo to give the title compound (100 mg, 78.80% yield, TFA) as a yellow solid. LC-MS (ESI ⁺ ) m/z 354.0 (M+H) ⁺ .

Step 5 - N-[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolinyl]-4-piperidinyl]-N-methyl- Tert-Butyl Carbamate

To a solution of 1-[8-[4-(methylamino)-1-piperidinyl]-4-isoquinolinyl]hexahydropyrimidine-2,4-dione (100 mg, 282 μmol) in DCM (1 mL) was added Et ₃ N (787 μL, 5.66 mmol) and Boc ₂ O (92.6 mg, 424 μmol) at 0° C., then the mixture was stirred at 25° C. for 13 h. Upon completion, the mixture was concentrated in vacuo to give a residue, which was then purified by reverse phase (0.1% FA condition) to give the title compound (70.0 mg, 54.55% yield) as a yellow solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ10.53(s,1H),9.45(s,1H),8.53(s,1H),7.75-7.68(m,1H),7.61(d,J＝8.4Hz,1H),7.28(d,J＝7.2Hz,1H),4.15-3.96(m,1H),3.92-3.86(m,1H),3.72-3.66(m,1H),3.48-3.41(m,2H),3.01-2.84(m,3H),2.81(s,3H),2.78-2.71(m,1H),2.19-2.02(m,2H),1.72-1.70(m,2H),1.43(s,9H)。 LC-MS(ESI ⁺ )m/z 454.1(M+H) ⁺ .

Step 6-1-[8-[4-(Methylamino)-1-piperidinyl]-4-isoquinolyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolinyl]-4-piperidinyl]-N-methyl-carbamate (60 mg, 132 μmol) in DCM (1 mL) was added TFA (0.5 mL, 6.75 mmol), and the mixture was then stirred at 25° C. for 1 hour. Upon completion, the mixture was concentrated in vacuo to give the title compound (58.0 mg, 93.79% yield, TFA) as a yellow solid. LC-MS (ESI ⁺ ) m/z 354.0 (M+H) ⁺ .

1-[8-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]-4-isoquinolyl]hexahydropyrimidine-2,4-diol Ketone (Intermediate GP)

Step 1-4-[[[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolinyl]-4-piperidinyl]-methyl- tert-Butyl]amino]methyl]piperidine-1-carboxylate

To a solution of 1-[8-[4-(methylamino)-1-piperidinyl]-4-isoquinolinyl]hexahydropyrimidine-2,4-dione (100 mg, 213 μmol, TFA, intermediate GO) in THF (1 mL) was added TEA (29.8 μL, 214 μmol). Then tert-butyl 4-formylpiperidine-1-carboxylate (41.0 mg, 192 μmol, CAS# 137076-22-3) and HOAc (12.2 μL, 214 μmol) were added, and the mixture was stirred at -10 °C for 0.5 hr. Then NaBH(OAc) ₃ (68.0 mg, 321 μmol) was added, and the mixture was stirred at -10 °C for 1.5 hr. Upon completion, the mixture was quenched with water (1 mL) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 5%-35%, 15 min) to give the title compound (70.0 mg, 59% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.53 (s, 1H), 9.43 (s, 1H), 8.53 (s, 1H), 7.75-7.68 (m, 1H), 7.61 (d, J = 8.4Hz, 1H), 7.26 (d, J = 7.6Hz, 1H), 4.00-3.85 (m, 3H), 3. 72-3.66(m,1H),3.50-3.43(m,2H),3.00-2.92(m,2H),2.88-2.65(m,6H),2.53-2.51(m,4H),2.05-1.87(m,4H),1.75-1.72(m,3H),1.40(s,9H),1 .11-0.94(m,2H). LC-MS(ESI ⁺ )m/z 551.4(M+H) ⁺ .

Step 2-1-[8-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]-4-isoquinolyl]hexahydropyrimidine- 2,4-Dione

To a solution of tert-butyl 4-[[[1-[4-(2,4-dioxohexahydropyrimidin-1-yl)-8-isoquinolinyl]-4-piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylate (35.0 mg, 63.5 μmol) in DCM (0.5 mL) was added HCl/dioxane (3 M, 0.5 mL) and the mixture was then stirred at 25 °C for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (30.0 mg, 97% yield, HCl) as a yellow solid. LC-MS (ESI ⁺ ) m/z 451.2 (M+H) ⁺ .

1-[8-[4-(Methylamino)-1-piperidinyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (Medium Intermediate GQ)

Step 1-N-[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]imidazo [1,2-a]pyridin-8-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester

1-(8-Bromoimidazo[1,2-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (600 mg, 1.40 mmol, synthesized via step 1-2 of intermediate BN), tert-butyl N-methyl-N-(4-piperidinyl)carbamate (449 mg, 2.10 mmol), Cs ₂ CO ₃ (1.37 g, 4.19 mmol), PD-PEPPSI-I HeptCl ₃ -chloropyridine (67.9 mg, 69.8 μmol) and A solution of molecular sieves (50 mg) in dioxane (15 mL) was stirred at 100 °C under _N2 for 16 hr. Upon completion, the reaction mixture was diluted with EtOAc (40 mL) and washed with water (30 mL x 3). The organic layer was dried over _Na2SO4 and concentrated in vacuo. The residue was triturated with water (20 _mL ) at 25 °C for 10 min to give the title compound (780 mg, 99% yield) as a brown solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.78(d,J＝6.4Hz,1H),7.47(s,1H),7.24(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,2H),6.84-6.79(m,1H),6.54(d,J＝7.2Hz,1H),4.81( s,2H),4.11-3.92(m,1H),3.83-3.75(m,2H),3.72(s,3H),2.93-3.06(m,2H),2.78-2.66(m,7H),1.90-1.81(m,2H),1.65(d,J＝9.6Hz,2H),1.41(s,9 H).

Step 2-1-[8-[4-(Methylamino)-1-piperidinyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4- Diketone

A solution of N-[1-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]imidazo[1,2-a]pyridin-8-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester (200 mg, 355 μmol) and TfOH (680 mg, 4.53 mmol) in TFA (2 mL) was stirred at 70° C. for 1 hr. After completion, the reaction mixture was concentrated in vacuo to give the title compound as a red oil (162 mg, 99% yield, TFA). LC-MS (ESI ⁺ ) m/z 343.2 (M+H) ⁺ .

1-[8-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]imidazo[1,2-a]pyridin-3-yl]hexahydro Pyrimidine-2,4-dione (Intermediate GR)

Step 1-4-[[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-8-yl]-4-piperidin- [piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of 1-[8-[4-(methylamino)-1-piperidinyl]imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (162 mg, 354 μmol, TFA, intermediate GQ), TEA (71.8 mg, 709 μmol), HOAc (63.9 mg, 1.06 mmol) in DMF (1 mL) and THF (1.5 mL) was added tert-butyl 4-formylpiperidine-1-carboxylate (113 mg, 532 μmol) and the mixture was stirred at 25° C. for 0.5 hr. Then, NaBH(OAc) ₃ (150 mg, 709 μmol) was added to the above mixture and stirred at 25° C. for 1 hr. Upon completion, the mixture was quenched with water (0.2 mL) and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (143 mg, 74% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.75 (s, 1H), 8.93-8.74 (m, 1H), 8.32-8.00 (m, 1H), 7.98-7.60 (m, 1H), 7.12-6.90 (m, 1H), 4.31-4.07 (m, 1H), 4.00-3.92 (m, 2H), 3.85-3.75 (m, 2H), 3.51-3.4 6(s,2H),3.22-3.12(m,1H),3.00-2.92(m,1H),2.88-2.69(m,9H),2.19-2.06(m,2H),2.00-1.80(m,4H),1.68(d,J＝11.6Hz,1H),1.40(s,9H),1.1 9-1.05(m,2H).

Step 2-1-[8-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]imidazo[1,2-a]pyridine-3- 2,4-dione

A mixture of tert-butyl 4-[[[1-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-8-yl]-4-piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylate (76.0 mg, 140 μmol) in HCl/EtOAc (2 mL) was stirred at 25° C. for 1 hr. After completion, the reaction mixture was concentrated in vacuo to give the title compound as a yellow solid (67 mg, 99% yield, HCl). LC-MS (ESI ⁺ ) m/z 440.3 (M+H) ⁺ .

3-[3-Methyl-2-oxo-4-[4-[2-(4-piperidinyl)ethyl]piperazin-1-yl]benzimidazol-1-yl]piperidine- 2,6-dione (Intermediate GS)

Step 1-4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]piperazine-1- Tert-Butyl Formate

To a solution of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate H) and tert-butyl piperazine-1-carboxylate (550 mg, 2.96 mmol) in dioxane (10 mL) were added 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (254 mg, 295 μmol, CAS#1435347-24-2) and Cs ₂ CO ₃ (963 mg, 2.96 mmol). The mixture was stirred at 100 °C under N ₂ atmosphere for 16 hr. Upon completion, the reaction mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (200 mg, 28% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 444.2 (M+H) ⁺ .

Step 2-3-[3-methyl-2-oxo-4-[4-[2-(4-piperidinyl)ethyl]piperazin-1-yl]benzimidazole-1- 1-[4-[[(4-[[[[piperidin-2,6-dione]]]]]

To a solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (80.0 mg, 144 μmol) in DCM (1 mL) was added TFA (16.5 mg, 144 μmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (70 mg, 86% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 344.0 (M+H) ⁺ .

3-[3-methyl-2-oxo-4-[4-[2-(4-piperidinyl)ethyl]piperazin-1-yl]benzimidazol-1-yl]piperidin- 2,6-Diketone (Intermediate GT)

Step 1-4-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]piperidinyl [tert-butyl]oxazin-1-yl]ethyl]piperidine-1-carboxylate

To a solution of 3-(3-methyl-2-oxo-4-piperazin-1-yl-benzoimidazol-1-yl)piperidine-2,6-dione (77.0 mg, 224 μmol, intermediate GS) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (56.1 mg, 246 μmol, CAS# 142374-19-4) in THF (1 mL) and DMF (0.2 mL) was added KOAc (220 mg, 2.24 mmol). The mixture was stirred at 0° C. for 6 min. NaBH(OAc) ₃ (95.1 mg, 448 μmol) was then added and the mixture was stirred at 0° C. for 1 hr. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 13%-43%, 10 min) to give the title compound (80 mg, 64% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 555.3 (M+H) ⁺ .

Step 2-3-[3-methyl-2-oxo-4-[4-[2-(4-piperidinyl)ethyl]piperazin-1-yl]benzimidazole-1- 1-[4-[[(4-[[[[piperidin-2,6-dione] ...

To a solution of tert-butyl 4-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]piperazin-1-yl]ethyl]piperidine-1-carboxylate (80.0 mg, 144 μmol) in DCM (1 mL) was added TFA (16.4 mg, 144 μmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (70 mg, 85% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 455.4 (M+H) ⁺ .

4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperidin (1-oxazin-1-ylpropyl)benzenesulfonamide (Intermediate GU)

Step 1-4-[3-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3- Methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(3-aminopropyl)piperazine-1-carboxylate (50.0 mg, 205 μmol, CAS# 373608-48-1) in a mixed solution of ACN (2 mL) and DMSO (0.5 mL) was added DIEA (53.1 mg, 410 μmol) and 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (139 mg, 308 μmol, Intermediate CW). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated in vacuo to remove the solvent. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10μm; mobile phase: [water( _NH4HCO3 )-ACN]; _B %: 46%-76%, 8min) to give the title compound (130 mg, 95% yield) as a white ^solid.1H NMR (400MHz, DMSO- _d6 )δ9.68(s,1H),8.75(s,1H),8.18(s,1H),7.72(d,J＝8.4Hz,1H),7.68(d,J＝1.6Hz,1H),7.67-7.59(m,1H),7.53(t,J＝5.6Hz,1H),5.78-5.67(m,1H),3 .27-3.19(m,4H),2.78(q,J=6.4Hz,2H),2.33(s,3H),2.25-2.21(m,2H),2 .21-2.16(m,4H),2.15-2.06(m,2H),1.69(s,4H),1.56-1.48(m,2H),1.46 (s,2H),1.36(s,9H). LCMS(ESI ⁺ )m/z 660.1(M+H) ⁺ .

Step 2-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N- (3-Piperazin-1-ylpropyl)benzenesulfonamide

To a solution of tert-butyl 4-[3-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]propyl]piperazine-1-carboxylate (80.0 mg, 121 μmol) in DCM (1.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated in vacuo to give the title compound (80.0 mg, 97% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 560.2 (M+H) ⁺ .

3-(3-Methyl-2-oxo-5-piperazin-1-yl-benzoimidazol-1-yl)piperidine-2,6-dione (Intermediate GV)

Step 1-4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperazine-1- Tert-Butyl Formate

3-(5-Bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (1.00 g, 2.96 mmol, intermediate J), tert-butyl piperazine-1-carboxylate (1.32 g, 5.91 mmol, CAS#57260-71-6), A mixture of molecular sieves, RuPhos (275 mg, 591 μmol), and [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane (459 mg, 591 μmol) in toluene (10 mL) was degassed and purged with N ₂ three times, and then the mixture was stirred at 25 ° C. under N ₂ atmosphere for 30 minutes. LiHMDS (1M, 10.3 mL) was then slowly added to the mixture. The mixture was then stirred at 80 ° C. under N ₂ atmosphere for 2 hours. After completion, the mixture was diluted with DMF (25 mL), and pH=5 was adjusted with FA, then filtered with DCM and concentrated in vacuo. The crude product was triturated with PE:EA=1:1 (10 mL) at 25 ° C. for 30 minutes, then filtered to give the title compound (820 mg, 57% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.07 (s, 1H), 6.97 (d, J = 8.4Hz, 1H), 6.88 (d, J = 2.0Hz, 1H), 6.66 (dd, J = 2.0, 8.4Hz, 1H), 5.30 (dd, J = 5.2, 12.8Hz, 1H), 3.50-3.47 ( m,4H),3.31(s,3H),3.06-3.02(m,4H),2.90(s,1H),2.63(s,1H),2.53(d,J＝2.0Hz,2H),1.43(s,9H). LC-MS(ESI ⁺ )m/z 444.1(M+H) ⁺ .

Step 2-3-(3-methyl-2-oxo-5-piperazin-1-yl-benzoimidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperazine-1-carboxylate (100 mg, 225 μmol) in DCM (1 mL) was added HCl/dioxane (4 M, 1 mL). The mixture was then stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the desired product as a white solid (76 mg, 88% yield, HCl). LC-MS (ESI ⁺ ) m/z 343.9 (M+H) ⁺ .

3-[5-[4-[[4-(2-aminoethoxy)cyclohexyl]methyl]piperazin-1-yl]-3-methyl-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate GW)

Step 1-N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5- tert-butyl]piperazin-1-yl]methyl]cyclohexyloxy]ethyl]carbamate

To a solution of 3-(3-methyl-2-oxo-5-piperazin-1-yl-benzoimidazol-1-yl)piperidine-2,6-dione (50 mg, 131 μmol, HCl, intermediate GV), and tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate (35.7 mg, 131 μmol, intermediate DP) in THF (0.5 mL) and DMF (0.5 mL) was added KOAc (129 mg, 1.32 mmol) and NaBH(OAc) ₃ (55.8 mg, 263 μmol). The mixture was then stirred at 25° C. for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The crude product was then purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 7%-37%, 9 min) to give the title compound (65 mg, 82% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 599.3 (M+H) ⁺ .

Step 2-3-[5-[4-[[4-(2-aminoethoxy)cyclohexyl]methyl]piperazin-1-yl]-3-methyl-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperazin-1-yl]methyl]cyclohexyloxy]ethyl]carbamate (55.0 mg, 91.8 μmol) in DCM (1 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was then stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (45.0 mg, 79% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 499.1 (M+H) ⁺ .

3-[5-(azetidin-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (intermediate GX)

Step 1-3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]azetidine tert-Butyl 1-oxanecarboxylate

To a solution of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate J), tert-butyl 3-bromoazetidine-1-carboxylate (453 mg, 1.92 mmol, CAS# 1064194-10-0) in DME (2 mL) was added Ir[dF( _CF3 )ppy] ₂ (dtbpy)( _PF6 ) (16.5 mg, 14.7 μmol), TTMSS (367 mg, 1.48 mmol), 2,6-lutidine (316 mg, 2.96 mmol) and _NiCl2.dtbbpy (22 μmol). The reaction was stirred and irradiated with a purple 10 W LED lamp (3 cm away) while maintaining the reaction temperature at 25°C with cooling water for 14 hr. After completion, the reaction mixture was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water(FA)-ACN]; B%: 25%-55%, 20min) to give the title compound (600mg, 97% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10 (s, 1H), 7.21 (d, J = 1.2Hz, 1H), 7.10-7.07 (m, 1H), 6.99 (dd, J = 1.2, 8.0Hz, 1H), 5.36 (dd, J = 5.2, 12.8Hz, 1H), 4.29-4.23 (m, 2 H),3.86(s,2H),3.84-3.78(m,1H),3.36(s,3H),2.96-2.85(m,1H),2.78-2.71(m,1H),2.67-2.62(m,1H),2.04-1.97(m,1H),1.41(s,9H). LC-MS(ESI ⁺ )m/z 359.6(M+H) ⁺ .

Step 2-3-[5-(azetidin-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dihydro- ketone

To a solution of tert-butyl 3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]azetidine-1-carboxylate (100 mg, 241 μmol) in DCM (1 mL) was added HCl/dioxane (4 M, 1 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give the desired product (84 mg, 99% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 314.9 (M+H) ⁺ .

3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]azetidin-3-yl]-3-methyl-2-oxo- [Benzimidazol-1-yl]piperidine-2,6-dione (Intermediate GY)

Step 1-N-[2-[4-[[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5- tert-butyl]azetidin-1-yl]methyl]cyclohexyloxy]ethyl]carbamate

To a solution of 3-[5-(azetidin-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (55 mg, 156. μmol, HCl, intermediate GX), tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate (50 mg, 184 μmol, intermediate DP) in DMF (0.5 mL) and THF (0.5 mL) was added KOAc (180 mg, 1.84 mmol) and NaBH(OAc) ₃ (78.1 mg, 368 μmol). The mixture was then stirred at 25° C. for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The crude material was then purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 7%-37%, 9 min) to give the title compound (55 mg, 52% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 570.3 (M+H) ⁺ .

Step 2-3-[5-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]azetidin-3-yl]-3-methyl- 2-Oxo-benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]azetidin-1-yl]methyl]cyclohexyloxy]ethyl]carbamate (55.0 mg, 96.5 μmol) in DCM (0.5 mL) was added TFA (651 mg, 5.71 mmol). The mixture was then stirred at 25 °C for 0.5 hours. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (50.0 mg, 89% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 470.1 (M+H) ⁺ .

3-[3-methyl-4-[3-(methylamino)azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2- 6-Diketone (Intermediate GZ)

Step 1-N-[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]azepine Cyclobutane-3-yl]-N-methyl-carbamic acid benzyl ester

A mixture of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (500 mg, 1.48 mmol, intermediate H), 3-(azetidin-3-yl)-N-methyl-carbamic acid benzyl ester (651 mg, 2.96 mmol), DABCO (165 mg, 1.48 mmol, 162 μL), NiBr ₂ .ethylene glycol dimethyl ether (324 mg, 1.05 mmol) and Ir(ppy) ₂ (dtbbpy) PF ₆ (1.35 g, 1.48 mmol) in DMA (15 mL) was degassed three times. The reaction vial was then sealed with a parafilm, placed 2 cm away from a blue LED, and irradiated at 25° C. for 14 hr. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1), (Rf = 0.50, PE:EA = 1:1) to give the title compound (620 mg, 87% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08 (d, J = 6.0 Hz, 1H), 7.42-7.26 (m, 3H), 7.18 (d, J = 7.6 Hz, 1H), 7.14-6.90 (m, 3H), 6.76-6.75 (m, 1H), 5.44-5.26 (m, 1H), 5.0 9(s,1H),4.02(t,J＝6.8Hz,1H),3.86(d,J＝6.0Hz,1H),3.66-3.52(m,2H), 3.34(s,3H),2.99(s,2H),2.94(s,3H),2.74-2.68(m,2H),2.68-2.62(m,2H ). LC-MS(ESI ⁺ )m/z477.9(M+H) ⁺ .

Step 2-3-[3-methyl-4-[3-(methylamino)azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidin-1-yl Pyridine-2,6-dione

A mixture of N-[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]azetidin-3-yl]-N-methyl-carbamic acid benzyl ester (200 mg, 418 μmol), Pd/C (20.0 mg, 4.19 μmol, 10 wt%) in THF (1.5 mL) was degassed and purged with _H 3 times. The mixture was then stirred at 25 °C under _H atmosphere for 1 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (140 mg, 97% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 343.8 (M+H) ⁺ .

3-[3-methyl-4-[3-[methyl(4-piperidinylmethyl)amino]azetidin-1-yl]-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate HA)

Step 1-4-[[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]nitrogen Heterocyclobutan-3-yl]-methyl-amino]methyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of 3-[3-methyl-4-[3-(methylamino)azetidin-1-yl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (140 mg, 407 μmol, intermediate GZ) and tert-butyl 4-formylpiperidine-1-carboxylate (86.9 mg, 407 μmol, CAS# 137076-22-3) in a mixed solvent of DMF (1 mL) and THF (1 mL) was added KOAc (400 mg, 4.08 mmol). The mixture was stirred at 0°C for 6 min. After that, NaBH(OAc) ₃ (172 mg, 815 μmol) was added to the above solution. The mixture was stirred at 0°C for 2.4 h. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) and then concentrated in vacuo. The mixture was purified by pre-HPLC (column: Phenomenex C18 150*25mm*10μm; mobile phase: [water(NH4HCO3)-CAN]; B%: 33%-63%, 8 min) to give the title compound (22 mg, 10% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 541.2 (M+H) ⁺ .

Step 2-3-[3-methyl-4-[3-[methyl(4-piperidinylmethyl)amino]azetidin-1-yl]-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]azetidin-3-yl]-methyl-amino]methyl]piperidine-1-carboxylate (22.0 mg, 40.6 μmol) in DCM (2 mL) and TFA (2 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (17.0 mg, 75% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 441.0 (M+H) ⁺ .

7'-Cyclopentyl-2'-methanesulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (intermediate HB)

Step 1-2-[4-(Cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]acetic acid ethyl ester

To a solution of ethyl 2-(4-chloro-2-methylsulfanyl-pyrimidin-5-yl)acetate (1.00 g, 4.05 mmol, CAS#61727-34-2) in dioxane (10 mL) was added cyclopentylamine (690 mg, 8.11 mmol, CAS#1003-03-8) and TEA (820 mg, 8.11 mmol). The mixture was stirred at 60 °C for 1 hr. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 °C and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1.10 g, 91% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.81(s,1H),5.73(d,J＝6.0Hz,1H),4.47-4.39(m,1H),4.14(q,J＝7.2Hz,2H),3.31(s,2H),2.51(s,3H),2.12-2.03(m,2H),1.78 -1.71(m,2H),1.68-1.61(m,2H),1.53-1.44(m,2H),1.25(t,J＝7.2Hz,3H). LC-MS(ESI ⁺ )m/z 296(M+H) ⁺ .

Step 2-7-Cyclopentyl-2-methylsulfanyl-5H-pyrrolo[2,3-d]pyrimidin-6-one

To a solution of ethyl 2-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]acetate (1.00 g, 3.39 mmol) in THF (10 mL) was added t-BuOK (1.14 g, 10.1 mmol). The mixture was stirred at 35 °C for 1 hr. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 °C and then extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (800 mg, 94% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 250.0 (M+H) ⁺ .

Step 3-7'-Cyclopentyl-2'-methylsulfanyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one

To a suspension of NaH (5.01 g, 125 mmol, 60% dispersion in mineral oil) in THF (5 mL) was added a solution of 1,2-dibromoethane (11.7 g, 62.5 mmol, CAS #106-93-4) in THF (5 mL) dropwise and the reaction mixture was stirred at 0°C for 30 min. Subsequently, 7-cyclopentyl-2-methylsulfanyl-5-H pyrrolo[2,3-d]pyrimidin-6-one (7.80 g, 31.2 mmol) was added and the reaction mixture was heated to 50°C for 1 hr. Upon completion, the reaction mixture was quenched with 1 M aqueous HCl solution (10 mL) at 25°C and then extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (7.5 g, 87% yield) as a pink solid. LC-MS (ESI ⁺ ) m/z 276.0 (M+1) ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (s, 1H), 4.89-4.80 (m, 1H), 2.57 (s, 3H), 2.29-2.20 (m, 2H), 2.02-1.89 (m, 4H), 1.79 (q, J=4.4 Hz, 2H), 1.71-1.63 (m, 2H), 1.58 (q, J=4.0 Hz, 2H).

Step 4-7'-Cyclopentyl-2'-methanesulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one

To a solution of 7'-cyclopentyl-2'-methylsulfanyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (5.15 g, 18.7 mmol) in DCM (50 mL) was added m-CPBA (11.3 g, 56.1 mmol, 85%) and the mixture was stirred at 40°C for 16 hr. Upon completion, the reaction mixture was quenched with H ₂ O (30 mL) at 25°C and then extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 0/1) to give the title compound (3.00 g, 52% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.05(s,1H),4.96-488(m,1H),3.34(s,3H),2.23-2.16(m,2H),2.05-2.00(m,2H),2.00-1.95(m,4H),1.82-1.78(m,2H),1.72- 1.67(m,2H). LC-MS(ESI ⁺ )m/z 307.7(M+1) ⁺ .

4-[(7'-cyclopentyl-6'-oxo-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-2'-yl)amino]- 3-Methyl-benzenesulfonyl chloride (intermediate HC)

Step 1-2'-(4-Benzylthio-2-methyl-phenylamino)-7'-cyclopentyl-spiro[cyclopropane-1,5'-pyrrolo] [2,3-d]pyrimidin-6'-one

7'-Cyclopentyl-2'-methanesulfonyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (1.00 g, 3.25 mmol, intermediate HB), 4-benzylsulfanyl-2-methyl-aniline (895 mg, 3.90 mmol, intermediate DE), A mixture of molecular sieves (3.25 mmol), Cs ₂ CO ₃ (3.18 g, 9.76 mmol), Pd(OAc) ₂ (73.0 mg, 325 μmol) and BINAP (405 mg, 650 μmol) in toluene (10 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 ° C. under N ₂ atmosphere for 12 hours. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 55%-85%, 17 min) to give the title compound (300 mg, 20% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 457.2 (M+1) ⁺ .

Step 2-4-[(7'-cyclopentyl-6'-oxo-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidine]-2'-yl) [amino]-3-methyl-benzenesulfonyl chloride

To a solution of 2'-(4-benzylsulfanyl-2-methyl-phenylamino)-7'-cyclopentyl-spiro[cyclopropane-1,5'-pyrrolo[2,3-d]pyrimidin]-6'-one (85.0 mg, 186 μmol2) in H ₂ O (0.12 mL), ACN (2 mL) and AcOH (0.2 mL) was added NCS (74.5 mg, 558 μmol). The mixture was stirred at 25° C. for 1 hr. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25° C. and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 1/1) to give the title compound (80 mg, 99% yield) as a white solid. LC-MS(ESI ⁺ )m/z 433.0(M+1) ⁺ .

Tert-butyl N-[4-(2-oxoethoxy)cyclohexyl]carbamate (Intermediate HD)

To a solution of tert-butyl N-[4-(2-hydroxyethoxy)cyclohexyl]carbamate (500 mg, 1.93 mmol, synthesized via step 1-2 of intermediate GH) in DCM (5 mL), DMP (1.23 g, 2.89 mmol, 895 μL) was added. The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was quenched with Na ₂ S ₂ O ₃ (20 mL), extracted with DCM (20 mL×3), washed with NaHCO ₃ (20 mL×3), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 2/1) (Rf=0.50, PE:EA=1:1) to give the title compound (490 mg, 98% yield) as a brown oily liquid. ^1. 37(s, _9H ),1.17(dd,J=6.0,12.8Hz,4H).

3-[5-[1-[2-(4-aminocyclohexyloxy)ethyl]-4-piperidinyl]-3-methyl-2-oxo-benzimidazole-1- [4-(2-[4-[4-piperidin-2,6-dione)]]

Step 1-N-[4-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5- tert-butyl]-1-piperidinyl]ethoxy]cyclohexyl]carbamate

To a solution of tert-butyl N-[4-(2-oxoethoxy)cyclohexyl]carbamate (150 mg, 582 μmol, intermediate HD) and 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (186 mg, 408 μmol, TFA, intermediate DB) in a mixed solvent of DMF (1 mL) and THF (1 mL) was added KOAc (572 mg, 5.83 mmol). The mixture was stirred at 0°C for 6 min. Thereafter, NaBH(OAc) ₃ (247 mg, 1.17 mmol) was added to the above mixture. The mixture was then stirred at 0°C for 2.4 hr. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) and then concentrated in vacuo. The mixture was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 11%-41%, 9 min) to give the title compound (80.0 mg, 23% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 584.2 (M+H) ⁺ .

Step 2-3-[5-[1-[2-(4-aminocyclohexyloxy)ethyl]-4-piperidinyl]-3-methyl-2-oxo-benzimidazole oxazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[4-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]ethoxy]cyclohexyl]carbamate (100 mg, 171 μmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (20.0 mg, 19% yield, TFA) as a white solid. LC-MS (ESI ⁺ ) m/z 484.1 (M+H) ⁺ .

1-[7-(4-piperidinyl)-4-isoquinolyl]hexahydropyrimidine-2,4-dione (Intermediate HF)

Step 1-4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinoline-7-yl tert-Butyl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of 1-(7-chloroisoquinolin-4-yl)-3-(4-methoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (150 mg, 378 μmol, synthesized via step 1-2 of intermediate BM) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (140 mg, 454 μmol, CAS _# 286961-14-6) in dioxane (2.0 mL) and water (0.2 mL) was added Xphos Pd _G2 (29.8 mg, 37.8 μmol) and _K3PO4 (160 mg, 757 μmol). The mixture was then stirred at 80 °C for 6 hours. After completion, the reaction solution was diluted with water (20 mL) and then extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and vacuum filtered. The residue was purified by prep-TLC to give the title compound (170 mg, 67% yield) as a brown oil. LC-MS (ESI ⁺ ) m/z 543.4 (M+H) ⁺ .

Step 2-4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinoline-7-yl tert-Butyl)piperidin-1-carboxylate

To _{a solution} of tert-butyl 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-7-yl)-5,6-dihydropyridine-1(2H)-carboxylate (160 mg, 294 μmol) in THF (20 mL) under N was added Pd/C (30 mg, 294 μmol, 10 wt%). The mixture was stirred at 20 °C under _H balloon (15 psi) for 1 h. Upon completion, the mixture was filtered through celite followed by washing with THF (50 mL). The filtrate was concentrated in vacuo to afford the title compound (130 mg, 72% yield) as a brown oil. ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.26(s,1H),8.49(s,1H),8.06(s,1H),7.85(d,J＝8.4Hz,1H),7.75(dd,J＝1.6,8.8Hz,1H),7.25(d,J＝8.8Hz,2H),6.90-6.86(m,2H),4.83(s,2H),4. 13(d,J＝11 .0Hz,2H),3.94-3.91(m,1H),3.73(s,3H),3.66-3.54(m,4H),3.15-3.08(m,1H),3.02-2.97(m,1H),1.88-1.85(m,2H),1.68-1.57(m,2H),1.35(s ,9H); LC-MS(ESI ⁺ )m/z 545.2(M+H) ⁺ .

Step 3-1-(7-(piperidin-4-yl)isoquinolin-4-yl)dihydropyrimidine-2,4(1H,3H)-dione

A solution of tert-butyl 4-(4-(3-(4-methoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)isoquinolin-7-yl)piperidine-1-carboxylate (40.0 mg, 73.4 μmol) in TFA (1.0 mL) and TfOH (0.05 mL) was stirred at 70° C. for 3 hours. Upon completion, the residue was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18, 150 mm*25 mm*10 μm; mobile phase: [water (0.225% FA)-MeCN]; B%: 1%-15%, 11.5 min) and then further purified by Prep-HPLC (column: Waters xbridge, 150 mm*25 mm*10 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ )-MeCN]; B%: 0%-26%, 11 min) to give the title compound (1.03 mg, 4% yield) as a white solid. ¹ HNMR(DMSO-d ₆ ,400Hz) δ10.53(s,1H),9.26(s,1H),8.48(s,1H),8.01(s,1H),7.92(d,J＝8.8Hz,1H),7.77-7.74(m,1H),3.96-3.89(m,1H),3.75-3 .69(m,1H),3.09(d,J＝12.0Hz,2H),3.00-2.72(m,4H),2.65-2.62(m,2H),1.80(d,J＝12Hz,2H),1.68-1.58(m,2H); LC-MS(ESI ⁺ )m/z 325.0(M+H) ⁺ .

1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidinyl]-4-isoquinolyl]hexahydropyrimidine- 2,4-Diketone (Intermediate HG)

Step 1-N-[2-[4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-7-isoquinolinyl]-1-piperidinyl] tert-Butyl]methyl]cyclohexyloxy]ethyl]carbamate

To a solution of 1-[7-(4-piperidinyl)-4-isoquinolinyl]hexahydropyrimidine-2,4-dione (134 mg, 305 μmol, TFA, intermediate HF), TEA (30.9 mg, 305 μmol) and HOAc (36.7 mg, 611 μmol) in DMF (1 mL) and THF (1 mL) was added tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate (82.9 mg, 305 μmol, intermediate DP) at -10°C. The mixture was stirred at -10°C for 0.5 hr. Then, NaBH(OAc) ₃ (97.1 mg, 458 μmol) was added to the above mixture at -10°C and the mixture was stirred at -10°C for 1 hr. After completion, the mixture was quenched with H ₂ O (0.05 mL). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 10%-40%, 15min) to give the title compound (100mg, 56% yield) as a white solid. ^1H NMR (400MHz, CDCl ₃ ) δ9.24(s,1H),8.52(s,1H),8.14(s,1H),7.92(d,J＝7.2Hz,2H),7.83-7.78(m,1H),7.76-7.71(m,1H),4.88(t,J＝4.8Hz,1H),4.04-3.97(m,1H),3.89-3.74(m,4H),3.52(t,J＝5.2Hz,2 H),3.29(d,J＝5.2Hz,2H),3.25-3.11(m,2H),3.07-2.89(m,7H),2.87-2.70(m,3H),2.63-2.41(m,3H),2.16-2.03(m,5H),1.97(d,J＝13.2Hz,2H),1. 89-1.78(m,1H),1.30-1.09(m,5H).

Step 2-1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidinyl]-4-isoquinolyl]hexa Hydropyrimidine-2,4-dione

A solution of tert-butyl N-[2-[4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-7-isoquinolinyl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]carbamate (100 mg, 172 μmol) in HCl/EtOAc (3 mL) was stirred at 25° C. for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound as a white solid (89 mg, 99% yield, HCl). LC-MS (ESI ⁺ ) m/z 480.1 (M+H) ⁺ .

1-[7-(4-Piperidinyl)imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (Intermediate HH)

Step 1-4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]piperidin-1-carboxylate Tert-butyl ester

To a 40 mL vial equipped with a stir bar was added a solution of 1-(7-bromoimidazo[1,2-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (498 mg, 1.61 mmol, intermediate AZ), tert-butyl 4-bromopiperidine-1-carboxylate (553 mg, 2.10 mmol, CAS# 180695-79-8), Ir[dF(CF3)ppy] ₂ (dtbpy)( _PF6 ) (36.1 mg, 32.2 μmol), _NiCl2 ·dtbbpy (19.2 mg, 48.3 μmol), TTMSS (400 mg, 1.61 mmol) and 2,6-lutidine (345 mg, 3.22 mmol) in DME (50 mL). The reaction was stirred and irradiated with 4×50W [455nm] blue LED lamps (3cm away) while keeping the reaction temperature at 25°C for 14hr with cooling water. After completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo. The crude product was purified by reverse phase (0.1% FA conditions) to give the title compound (220mg, 33% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.65(s,1H),8.24(d,J＝7.2Hz,1H),7.51(s,1H),7.38(s,1H),6.98-6.91(m,1H),4.16-4.02(m,2H),3.78(t,J＝6.8Hz,2H), 2.87-2.73(m,5H),1.82(d,J＝12.8Hz,2H),1.54(m,J＝4.4,12.4Hz,2H),1.42(s,9H).

Step 2-1-[7-(4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl 4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]piperidine-1-carboxylate (220 mg, 532 μmol) in HCl/EtOAc (4 mL) was stirred at 25° C. for 1 hr. Upon completion, the mixture was concentrated in vacuo to afford the title compound as a white solid (186 mg, 99% yield, HCl). LCMS (ESI ⁺ ) m/z 314.0 (M+H) ⁺ .

1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidinyl]imidazo[1,2-a]pyridine-3- [1,4-Dihydropyrimidine] (2,4-dione) (Intermediate HI)

Step 1-N-[2-[4-[[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridine-7-yl] tert-butyl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]carbamate

To a solution of 1-[7-(4-piperidinyl)imidazo[1,2-a]pyridin-3-yl]hexahydropyrimidine-2,4-dione (103 mg, 294 μmol, HCl, intermediate HH), TEA (29.8 mg, 294 μmol) and HOAc (35.4 mg, 589 μmol) in DMF (1 mL) and THF (1 mL) was added tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]carbamate (80 mg, 294 μmol, intermediate DP) at -10°C. The mixture was stirred at -10°C for 0.5 hr. Subsequently, NaBH(OAc) ₃ (93.7 mg, 442 μmol) was added to the above mixture at -10°C and the mixture was stirred at -10°C for 1 hr. After completion, the mixture was quenched with H ₂ O (0.05 mL). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 1%-30%, 15min) to give the title compound (70mg, 41% yield) as a white solid. ^1H NMR (400MHz, CDCl ₃ ) δ8.40(s,1H),7.79(d,J＝7.2Hz,1H),7.57(s,1H),7.51(s,1H),6.91(dd,J＝1.2,7.2Hz,1H),5.38-4.84(m,1H),3.89(t,J＝6.8Hz,2H),3.58-3.48(m,4H),3.28(d,J＝5.2Hz,2H),3.24-3.15(m,1 H),2.98-2.90(m,2H),2.82-2.68(m,3H),2.62-2.52(m,2H),2.37-2.24(m,2H),2.08(d,J＝10.4Hz,2H),1.95(d,J＝13.2Hz,4H),1.74(m,1H),1.45(s ,9H),1.28-1.18(m,2H),1.14-1.03(m,2H).

Step 2-1-[7-[1-[[4-(2-aminoethoxy)cyclohexyl]methyl]-4-piperidinyl]imidazo[1,2-a]pyrrolidone pyrimidine-3-yl]hexahydropyrimidine-2,4-dione

A solution of tert-butyl N-[2-[4-[[4-[3-(2,4-dioxohexahydropyrimidin-1-yl)imidazo[1,2-a]pyridin-7-yl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]carbamate (70.0 mg, 123 μmol) in HCl/EtOAc (3 mL) was stirred at 25° C. for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound as a white solid (60 mg, 96% yield, HCl). LCMS (ESI ⁺ ) m/z 469.4 (M+H) ⁺ .

tert-Butyl 6-(3-oxopropoxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate HJ)

Step 1-6-allyloxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.00 g, 4.69 mmol, CAS# 1147557-97-8) in DMF (20 mL) was added NaH (375 mg, 9.38 mmol, 60% purity) and 3-bromoprop-1-ene (850 mg, 7.03 mmol, CAS# 106-95-6). The mixture was then stirred at 0 °C for 3 hr. Upon completion, the reaction mixture was washed with brine (100 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20/1 to 5/1) to give the title compound (1.08 g, 90% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ5.99-5.84(m,1H),5.31-5.25(m,1H),5.21-5.17(m,1H),3.91(s,2H),3.90-3.87(m,5H),2.52-2.46(m,2H),2.17-2.10(m,2H) ,1.45(s,9H).

Step 2-tert-Butyl 6-(3-hydroxypropoxy)-2-azaspiro[3.3]heptane-2-carboxylate

To a solution of tert-butyl 6-allyloxy-2-azaspiro[3.3]heptane-2-carboxylate (1.08 g, 4.26 mmol) in THF (12 mL) was added 9-BBN (0.5 M, 25.58 mL) at 0°C. The mixture was then stirred at 25°C for 16 hr. The reaction solution was cooled to 0°C, followed by the addition of deionized water (1 mL) and NaOH (3 M, 6 mL). Afterwards, H ₂ O ₂ (4.77 g, 39.2 mmol, 28% solution) was added at 0°C and the mixture was stirred for 30 min. Upon completion, the mixture was diluted with water (10 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (800 mg, 69% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.89 (s, 2H), 3.86 (s, 2H), 3.84-3.77 (m, 3H), 3.75 (t, J=5.6 Hz, 2H), 3.49 (t, J=6.0 Hz, 2H), 2.51-2.42 (m, 2H), 2.11-2.03 (m, 2H), 1.42 (s, 9H).

Step 3-6-(3-oxopropoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl 6-(3-hydroxypropoxy)-2-azaspiro[3.3]heptane-2-carboxylate (200 mg, 737 μmol) in DCM (4 mL) was added DMP ( ₃₇₅ mg, 884 μmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was quenched _{with Na2S2O3·5H2O ( 10} mL) and then extracted with DCM (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=10/1 to 1/1) to give the title compound (90 mg, 45% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ9.79 (s, 1H), 4.35 (t, J = 5.2Hz, 2H), 3.90 (s, 2H), 3.87 (s, 3H), 3.65 (t, J = 6.0Hz, 2H), 2.68-2.62 (m, 2H), 2.47 (d, J = 6.4Hz, 2H), 1.4 4(s,9H).

3-[5-[1-[3-(2-azaspiro[3.3]hept-6-yloxy)propyl]-4-piperidinyl]-3-methyl-2-oxo-benzene [[(1-imidazol-1-yl]piperidine-2,6-dione) (Intermediate HK)

Step 1-6-[3-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]- 1-Piperidinyl]propoxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (60.0 mg, 131 μmol, TFA salt, intermediate DB) and tert-butyl 6-(3-oxopropoxy)-2-azaspiro[3.3]heptane-2-carboxylate (35.4 mg, 131 μmol, intermediate HJ) in a mixed solution of THF (2 mL) and DMF (0.5 mL) was added KOAc (129 mg, 1.31 mmol) and NaBH(OAc) ₃ (55.7 mg, 262 μmol). The mixture was stirred at 0° C. for 1 hr. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) at 0° C. and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex lunaC18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 12%-42%, 9 min) to give the title compound (50 mg, 63% yield) as a white solid. LCMS (ESI ⁺ ) m/z 596.5 (M+H) ⁺ .

Step 2-3-[5-[1-[3-(2-azaspiro[3.3]hept-6-yloxy)propyl]-4-piperidinyl]-3-methyl-2- [Oxo-benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 6-[3-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]propoxy]-2-azaspiro[3.3]heptane-2-carboxylate (50.0 mg, 83.9 μmol) in DCM (1 mL) was added TFA (2.31 g, 20.2 mmol). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (50.0 mg, 97% yield, TFA salt) as a white solid. LCMS (ESI ⁺ ) m/z 496.2 (M+H) ⁺ .

Benzyl N-[2-(4-piperidinyloxy)ethyl]carbamate (Intermediate HL)

Step 1-4-[2-(tert-Butyloxycarbonylamino)ethoxy]piperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-hydroxypiperidine-1-carboxylate (400 mg, 1.70 mmol, CAS#95798-23-5) in DMF (8 mL) was added NaH (136 mg, 3.40 mmol, 60% dispersion in mineral oil) portionwise at 0°C. The mixture was stirred at 0°C for 0.5 hr, followed by the addition of benzyl 2,2-dioxooxathiazolidin-3-carboxylate (437 mg, 1.70 mmol, CAS#1215021-54-7). The reaction mixture was stirred at 25°C for 15.5 hr. The reaction mixture was washed with brine (30 mL) and extracted with DCM (30 mL). _The organic layer was dried over anhydrous _Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 20/1 to 5/1) to give the title compound (300 mg, 46% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.33-7.20(m,5H),5.04(s,2H),3.69-3.65(m,2H),3.46(s,2H),3.16-3.08(m,2H),2.97-2.95(m,2H),2.90-2.80(m,1H),1. 64-1.56(m,2H),1.43(d,J＝4.4Hz,2H),1.39(s,9H). LCMS(ESI ⁺ )m/z 401.1(M+Na) ⁺ .

Step 2-Benzyl N-[2-(4-piperidinyloxy)ethyl]carbamate

To a solution of tert-butyl 4-[2-(benzyloxycarbonylamino)ethoxy]piperidine-1-carboxylate (110 mg, 290 μmol) in DCM (1.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated in vacuo to give the title compound as a colorless oil (110 mg, 96% yield, TFA). LCMS (ESI ⁺ ) m/z 279.2 (M+H) ⁺ .

3-[5-[4-[[4-(2-aminoethoxy)-1-piperidinyl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzene [[(1-( ...

Step 1-N-[2-[[1-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazole-5- Benzyl]-4-piperidinyl]methyl]-4-piperidinyl]oxy]ethyl]carbamate

To a solution of benzyl N-[2-(4-piperidinyloxy)ethyl]carbamate (110 mg, 280 μmol, TFA, intermediate HL) and 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidine-4-carbaldehyde (103 mg, 280 μmol, intermediate DM) in a mixed solution of THF (2 mL) and DMF (0.5 mL) was added KOAc (275 mg, 2.80 mmol) and NaBH(OAc) ₃ (118 mg, 560 μmol). The mixture was stirred at 0° C. for 1 hr. Upon completion, the mixture was quenched with H ₂ O (0.5 mL) at 0° C. and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex lunaC18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 0%-30%, 9 min) to give the title compound (60.0 mg, 33% yield) as a white solid. LCMS (ESI ⁺ ) m/z 633.5 (M+H) ⁺ .

Step 2-3-[5-[4-[[4-(2-aminoethoxy)-1-piperidinyl]methyl]-1-piperidinyl]-3-methyl-2-oxo [-Benzimidazol-1-yl]piperidine-2,6-dione

To a solution of _benzyl N-[2-[[1-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]methyl]-4-piperidinyl]oxy]ethyl]carbamate (60.0 mg, 94.8 μmol) in THF (3 mL) under N was added Pd/C (40.0 mg, 94.8 μmol, 10 wt%). The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred at 25 °C under _H (20 psi) for 1 hr. Upon completion, the reaction was filtered and the filtrate was concentrated in vacuo to give the title compound (30 mg, 63% yield) as a white solid. LCMS (ESI ⁺ ) m/z 499.2 (M+H) ⁺ .

8-Cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate HN)

Step 1-5-Bromo-2-chloro-N-cyclopentyl-pyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloro-pyrimidine (5.00 g, 21.9 mmol, CAS#36082-50-5) in dioxane (100 mL) was added cyclopentylamine (2.24 g, 26.3 mmol, CAS#1003-03-8). The mixture was stirred at 25 °C for 6 hr. Upon completion, the reaction mixture was treated with H ₂ O (100 mL) at 25 °C and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 1/1) to give the title compound (7.50 g, 61% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.36 (d, J = 7.2Hz, 1H), 4.35-4.26 (m, 1H), 1.92-1.88 (m, 2H), 1.72-1.65 (m, 2H), 1.63-1.51 (m, 4H).

Step 2-5-Bromo-N-cyclopentyl-2-methylsulfanyl-pyrimidin-4-amine

A solution of 5-bromo-2-chloro-N-cyclopentyl-pyrimidin-4-amine (2.00 g, 7.23 mmol) in DMF (20 mL) was degassed and purged with _N 3 times, then NaSMe (1.29 g, 18.4 mmol) was added to the mixture. The mixture was stirred at 25 °C under N ₂ atmosphere for 16 hr. Upon completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 °C and then extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude product was then purified by reverse phase HPLC (0.1% FA condition) to give the title compound (2.00 g, 95% yield) as an off-white oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.05 (s, 1H), 5.27 (d, J = 4.0 Hz, 1H), 4.44-4.36 (m, 1H), 2.50 (s, 3H), 2.15-2.07 (m, 2H), 1.78-1.63 (m, 4H), 1.53-1.45 (m, 2H).

Step 3-(E)-3-[4-(Cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoic acid methyl ester

A mixture of 5-bromo-N-cyclopentyl-2-methylsulfanyl-pyrimidin-4-amine (2.00 g, 6.94 mmol), TEA (2.11 g, 20.8 mmol), Pd(PPh ₃ ) ₄ (801 mg, 693 μmol) in DMF (20 mL) was degassed and purged with N ₂ three times. Then methyl prop-2-enoate (3.11 g, 36.1 mmol, CAS# 96-33-3) was added to the mixture, and then the mixture was stirred at 90 ° C under N ₂ atmosphere for 16 hours. After completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 ° C, and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was then purified by reverse phase HPLC (0.1% FA condition) to give the title compound (1.37 g, 67% yield) as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (s, 1H), 7.49 (d, J=16.0 Hz, 1H), 6.27 (dd, J=1.2, 15.6 Hz, 1H), 5.08 (d, J=6.0 Hz, 1H), 4.52-4.44 (m, 1H), 3.83-3.79 (m, 3H), 2.58-2.51 (m, 3H), 2.19-2.08 (m, 2H), 1.81-1.62 (m, 4H), 1.53-1.45 (m, 2H).

Step 4-8-Cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of (E)-3-[4-(cyclopentylamino)-2-methylsulfanyl-pyrimidin-5-yl]prop-2-enoic acid methyl ester (1.00 g, 3.41 mmol) in NMP (10 mL) was added DBU (2.59 g, 17.0 mmol). The mixture was stirred at 120 ° C for 1 hr. After completion, the reaction mixture was quenched with H ₂ O (20 mL) at 25 ° C and then extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 10/1) to give the title compound (484 mg, 54% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 262.0 (M+1) ⁺ .

4-[[8-cyclopentyl-6-(difluoromethyl)-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]-3-methyl- Benzenesulfonyl chloride (intermediate HO)

Step 1-6-[Chloro(difluoro)methyl]-8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a 40 mL vial equipped with a stir bar was added 8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 3.83 mmol, intermediate HN), (2-chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (2.09 g, 8.60 mmol, CAS# 2834-23-3), 1-oxonyl-4-phenyl-pyridin-1-ium (1.31 g, 7.65 mmol), and Ru(bpy) ₃ Cl ₂ .6H ₂ O (28.6 mg, 38.2 μmol) in anhydrous ACN (10 mL). The vial was sealed and placed under added nitrogen. The reaction was stirred and irradiated with 4×50 W [455 nm] blue LED lamps (3 cm away) while the reaction temperature was maintained at 25° C. with cooling water for 14 hr. After completion, the mixture was filtered and concentrated in vacuo. The residue was purified by prep-HPLC (column; mobile phase: [water (TFA) -ACN]; B%: 35% -85%, 30 min) to give the title compound (1.10 g, 83% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.04 (s, 1H), 8.51 (s, 1H), 5.87 (q, J = 8.8 Hz, 1H), 2.61 (s, 3H), 2.27-2.17 (m, 2H), 2.03-1.97 (m, 2H), 1.89-1.82 (m, 2H), 1.70-1.61 (m, 2H). LC-MS (ESI ⁺ ) m/z 346.0 (M+H) ⁺ .

Step 2-8-Cyclopentyl-6-(difluoromethyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-[chloro(difluoro)methyl]-8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (1.10 g, 3.18 mmol) in MeOH (12 mL) was added Na ₂ CO ₃ (505 mg, 4.77 mmol) and Pd/C (600 mg, 3.18 mmol, 10 wt %). The mixture was stirred at 25° C. under H ₂ (15 psi) for 4 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (990 mg, 99% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.02 (d, J = 6.0 Hz, 1H), 8.37-8.27 (m, 1H), 5.90-5.81 (m, 1H), 4.12 (s, 1H), 2.61-2.60 (m, 3H), 2.24-2.19 (m, 2H), 2.01-1.97 (m,2H),1.86-1.81(m,2H),1.67-1.62(m,2H). LC-MS(ESI ⁺ )m/z 311.9(M+H) ⁺ .

Step 3-8-Cyclopentyl-6-(difluoromethyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-6-(difluoromethyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (990 mg, 3.18 mmol) in DCM (10 mL) was added m-CPBA (968 mg, 4.77 mmol, 85% solution) at 0°C. The mixture was then stirred at 25°C for 8 hr. Upon _completion , the mixture was _{quenched with Na2S2O35H2O (} 50 mL), washed with _NaHCO3 solution (3×50 mL), _and extracted with DCM (3×50 mL). The organic layer was then washed with brine (3×50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , PE/EA=62/38) to give the title compound (500 mg, 4% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.41 (d, J = 4.8 Hz, 1H), 8.58-8.46 (m, 1H), 7.20-6.87 (m, 1H), 5.87-5.76 (m, 1H), 3.48-3.45 (m, 3H), 2.25-2.16 (m, 2H), 2.12 -2.05(m,2H),1.93-1.84(m,2H),1.70-1.62(m,2H). LC-MS(ESI ⁺ )m/z 344.0(M+H) ⁺ .

Step 4-2-(4-Benzylthio-2-methyl-phenylamino)-8-cyclopentyl-6-(difluoromethyl)pyrido[2,3- d]pyrimidin-7-one

To a solution of 8-cyclopentyl-6-(difluoromethyl)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one (500 mg, 1.46 mmol) and 4-benzylsulfanyl-2-methyl-aniline (667 mg, 2.91 mmol, intermediate DE) in i-PrOH (5 mL) was added TFA (1.66 g, 14.56 mmol). The mixture was stirred at 85 °C for 6 hr. Upon completion, the mixture was cooled to rt, diluted with H ₂ O (30 mL), and extracted with EA (3×30 mL). The combined organic phases were washed with brine (2×30 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE/EA=63/37) to give the title compound (195 mg, 27% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.63-9.58(s,1H),8.82(s,1H),8.11(s,1H),7.40-7.35(m,2H),7.33-7.25(m,5H),7.22-7.19(m,1H),7.02-6.74(m,1H), 5.78-5.48(m,1H),4.24(s,2H),2.17(s,3H),2.11-2.03(m,2H),1.65-1.36(m,6H). LC-MS(ESI ⁺ )m/z 493.1(M+H) ⁺ .

Step 5-4-[[8-cyclopentyl-6-(difluoromethyl)-7-oxo-pyrido[2,3-d]pyrimidin-2-yl]amino]- 3-Methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-8-cyclopentyl-6-(difluoromethyl)pyrido[2,3-d]pyrimidin-7-one (195 mg, 395 μmol) in a mixed solvent of ACN (2 mL), AcOH (200 μL) and H ₂ O (20 μL) was added NCS (158 mg, 1.19 mmol). The mixture was stirred at 25° C. under dark environment for 0.5 hr. After completion, the mixture was diluted with H ₂ O (5 mL), extracted with EA (3×10 mL). The organic layer was washed with brine (3×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the liquid was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE/EA=85/15) to give the title compound (165 mg, 88% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.61(s,1H),8.83(s,1H),8.12(s,1H),7.49(s,1H),7.46-7.40(m,1H),7.38-7.32(m,1H),7.04-6.74(m,1H),5.74-5.60( m,1H),2.22(s,3H),2.16-2.07(m,2H),1.74-1.60(m,4H),1.46-1.39(m,2H). LC-MS(ESI ⁺ )m/z468.7(M+H) ⁺ .

tert-Butyl N-[2-(3-formylcyclobutyloxy)ethyl]carbamate (Intermediate HP)

Step 1-3-(Benzyloxymethyl)cyclobutanol

To a solution of 3-(benzyloxymethyl)cyclobutanone (5.00 g, 26.2 mmol, CAS# 172324-67-3) in THF (50 mL) stirred at -70 °C was added a solution of lithium tri-sec-butylborate (9.99 g, 52.5 mmol) dropwise, maintaining the reaction temperature below -65 °C. The reaction mixture was allowed to warm to 25 °C for 16 hr. Upon completion, the reaction was quenched with saturated sodium bicarbonate (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were acidified with 2N aqueous HCl (30 mL) and stirred at 25 °C for 3 hr. The organic layers were then washed with brine (100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO ₂ , PE/EA=10/1) to give the title compound (3.50 g, 69% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.28(m,5H),4.55-4.51(m,2H),4.19-4.10(m,1H),3.48-3.43(m,2H),2.53-2.39(m,2H),2.15-2.07(m,1H),1.76-1.65( m,2H).

Step 2-[3-(Benzyloxymethyl)cyclobutyl]4-nitrobenzoate

To a solution of 3-(benzyloxymethyl)cyclobutanol (3.50 g, 18.2 mmol) and 4-nitrobenzoic acid (6.08 g, 36.4 mmol, CAS# 1044278-58-1) in THF (100 mL) was added _PPh3 (9.55 g, 36.4 mmol) at 0°C. Then a solution of DEAD (6.34 g, 36.4 mmol) in THF (60 mL) was added dropwise to the above solution. The mixture was degassed and purged with _N2 three times and the mixture was stirred at 25°C for 16 hr. Upon completion, the mixture was quenched with water (50 mL) and then extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and the organic liquid was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE/EA=92/8) to give the title compound (3.00 g, 48% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32-8.28 (m, 2H), 8.24-8.20 (m, 2H), 7.41-7.28 (m, 5H), 5.37 (q, J=6.8 Hz, 1H), 4.58 (s, 2H), 3.55 (d, J=6.4 Hz, 2H), 2.73-2.62 (m, 1H), 2.46-2.38 (m, 4H).

Step 3-3-(Benzyloxymethyl)cyclobutanol

To a solution of [3-(benzyloxymethyl)cyclobutyl]4-nitrobenzoate (3 g, 8.79 mmol) in a mixture of dioxane (30 mL) and H ₂ O (15 mL) was added LiOH.H ₂ O (737 mg, 17.5 mmol). The mixture was stirred at 25 °C for 1 hr. After completion, the mixture was diluted with H ₂ O (50 mL) and extracted with EA (3×50 mL). The organic layer was washed with brine (2×50 mL). Drying over anhydrous sodium sulfate, filtering and concentrating in vacuo gave the title compound as a colorless oil (1.69 g, 100% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.27(m,5H),4.54(s,2H),4.44-4.36(m,1H),3.47(d,J=7.2Hz,2H),2.58-2.43(m,1H),2.25-2.18(m,2H),2.11-2.03(m,2 H).

Step 4-Ethyl 2-[3-(benzyloxymethyl)cyclobutyloxy]acetate

To a solution of 3-(benzyloxymethyl)cyclobutanol (1.69 g, 8.79 mmol) in DCM (40 mL) was added diacetoxyrhodium (388 mg, 879 μmol) and ethyl 2-diazoacetate (4.01 g, 35.1 mmol, CAS #623-73-4). The mixture was degassed and purged with N ₂ three times and the mixture was stirred at 25 °C under N ₂ atmosphere for 16 hr. Upon completion, the mixture was diluted with H ₂ O (50 mL) and extracted with DCM (3×50 mL). The organic layer was then washed with brine (3×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE/EA=100/1 to 10/1) to give the title compound (2.40 g, 98% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.28(m,5H),4.53(s,2H),4.24(d,J＝3.2Hz,2H),4.17-4.14(m,1H),3.97(s,2H),3.46(d,J＝6.8Hz,2H),2.57-2.46(m,1H ),2.24-2.13(m,4H),1.31-1.29(m,3H).

Step 5-2-[3-(Benzyloxymethyl)cyclobutyloxy]acetamide

To a solution of ethyl 2-[3-(benzyloxymethyl)cyclobutoxy]acetate (2.40 g, 8.62 mmol) in MeOH (20 mL) was added NH ₃ .H ₂ O (35.6 g, 284 mmol, 28% solution). The mixture was stirred at 70 °C for 16 hr. Upon completion, the mixture was concentrated in vacuo, then dissolved in EA (20 mL), diluted with H ₂ O (30 mL), and extracted with EA (3×20 mL). The organic layer was then washed with brine (3×20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and the liquid concentrated in vacuo to give the title compound (1.60 g, 74% yield) as a brown solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.40-7.28(m,5H),6.53(s,1H),5.76(s,1H),4.54(s,2H),4.13(q,J＝6.4Hz,1H),3.84(s,2H),3.47(d,J＝6.4Hz,2H),2.60-2.4 8(m,1H),2.18-2.11(m,4H).

Step 6-2-[3-(Benzyloxymethyl)cyclobutyloxy]ethylamine

To a solution of 2-[3-(benzyloxymethyl)cyclobutyloxy]acetamide (1.60 g, 6.42 mmol) in THF (18 mL) was added BH ₃ -Me ₂ S (10 M, 6.42 mL) at 25° C. The mixture was then stirred at 60° C. for 16 hr. Upon completion, the mixture was quenched with MeOH (3×10 mL) and refluxed for 20 min (three times) before being concentrated in vacuo to give the title compound (1.50 g, 99% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 236.1 (M+H) ⁺ .

Step 7 - tert-Butyl N-[2-[3-(Benzyloxymethyl)cyclobutyloxy]ethyl]carbamate

To a solution of 2-[3-(benzyloxymethyl)cyclobutoxy]ethanamine (1.50 g, 6.37 mmol) in DCM (20 mL) was added TEA (967 mg, 9.56 mmol) and Boc ₂ O (1.53 g, 7.01 mmol). The mixture was stirred at 25 °C for 16 hr. After completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE/EA=40/1) to give the title compound (1.00 g, 46% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.38-7.25(m,5H),6.76(t,J＝5.2Hz,1H),4.47(s,2H),4.00(q,J＝6.8Hz,1H),3.42(d,J＝6.8Hz,2H),3.23(t,J＝6.0Hz,2H),3.02 (q,J＝6.0Hz,2H),2.42-2.33(m,1H),2.00-1.94(m,4H),1.37(s,9H).

Step 8 - tert-Butyl N-[2-[3-(Hydroxymethyl)cyclobutyloxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[3-(benzyloxymethyl)cyclobutoxy]ethyl]carbamate (430 mg, 1.28 mmol) in MeOH (5 mL) was added Pd/C (400 mg, 1.28 mmol, 10 wt%) and Pd(OH) ₂ (430 mg, 612 μmol, 20 wt%) under Ar atmosphere. The mixture was then stirred at 50 °C under H ₂ (50 psi) for 16 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (310 mg, 98% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.90 (s, 1H), 4.05 (q, J = 6.8Hz, 1H), 3.64 (d, J = 6.8Hz, 2H), 3.41-3.36 (m, 2H), 3.33-3.27 (m, 2H), 2.41 (q, J = 6.8, 13.6Hz, 1H), 2. 12-2.09(m,2H),1.79-1.54(m,2H),1.45(s,9H).

Step 9 - tert-Butyl N-[2-(3-formylcyclobutyloxy)ethyl]carbamate

To a solution of tert-butyl N-[2-[3-(hydroxymethyl)cyclobutoxy]ethyl]carbamate (310 mg, 1.26 mmol) in DCM (5 mL) was added DMP ( ₈₀₃ mg, 1.90 mmol). The mixture was stirred at 25 °C for 2 hr. Upon completion, the mixture _{was quenched with Na2S2O35H2O (} 10 mL), washed with _NaHCO3 solution (3 x 20 mL), and extracted with DCM (3 x 20 mL). The organic layer was washed with brine (3 x 20 mL), dried _over anhydrous _Na2SO4 , filtered and the liquid was concentrated in vacuo to give the title compound (307 mg, 99% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.72(d,J＝2.0Hz,1H),6.82-6.75(m,1H),4.07-3.93(m,1H),3.05-3.00(t,J＝6.0Hz,2H),3.05-3.00(m,2H),2.46-2.39(m,3 H),2.09-2.05(m,2H),1.37(s,9H).

3-[5-[1-[[3-(2-aminoethoxy)cyclobutyl]methyl]-4-piperidinyl]-3-methyl-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate HQ)

Step 1-N-[2-[3-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5- tert-butyl]-1-piperidinyl]methyl]cyclobutyloxy]ethyl]carbamate

To a solution of tert-butyl N-[2-(3-formylcyclobutyloxy)ethyl]carbamate (307 mg, 1.26 mmol, intermediate HP) and 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (575 mg, 1.26 mmol, TFA, intermediate DB) in a mixture of THF (8 mL) and DMF (2 mL) was added TEA (255 mg, 2.52 mmol). The mixture was stirred at -10 °C for 5 min. After that, AcOH (227 mg, 3.79 mmol) was added to the above solution and then the mixture was stirred at -10 °C for 25 min. Then NaBH(OAc) ₃ (534 mg, 2.52 mmol) was added and the mixture was stirred at -10 °C for 3.5 hr. After completion, the mixture was quenched with H ₂ O (3 mL) and then the mixture was concentrated in vacuo. The crude product was purified by reverse phase (0.1% TFA) to give the title compound (187 mg, 27% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.09 (s, 1H), 7.06 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J=8.0 Hz, 1H), 6.83-6.74 (m, 1H), 5.40-5.32 (m, 1H), 3.54-3.49 (m, 2H), 3.34 (s, 3H), 3.29-3.26 (m, 2H), 3.21-3.1 7(m,1H),3.09-3.00(m,4H),2.93-2.82(m,2H),2.73-2.66(m,1H),2.48-2.36(m,2H),2.26-2.18(m,1H),2.17-2.08(m,2H),2.02-1.87(m,6H),1 .74-1.60(m,2H),1.37(s,9H). LC-MS(ESI ⁺ )m/z 570.4(M+H) ⁺ .

Step 2-3-[5-[1-[[3-(2-aminoethoxy)cyclobutyl]methyl]-4-piperidinyl]-3-methyl-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[3-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]methyl]cyclobutoxy]ethyl]carbamate (80.0 mg, 140 μmol) in DCM (1 mL) was added TFA (308 mg, 2.70 mmol). The mixture was stirred at 25 °C for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (80.0 mg, 97% yield, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 470.1 (M+H) ⁺ .

3-[3-methyl-4-[methyl(4-piperidinylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidin-2,6-dione Ketone (Intermediate HR)

Step 1-4-[[Methyl-(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]piperidine-1-carboxylic acid Tert-butyl ester

4-Bromo-3-methyl-1H-benzimidazol-2-one (100 mg, 440 μmol, synthesized via steps 1-3 of Intermediate H), tert-butyl 4-(methylaminomethyl)piperidine-1-carboxylate (100 mg, 440 μmol, CAS#138022-02-3), Cs ₂ CO ₃ (287 mg, 880 μmol), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (38.0 mg, 44.0 μmol) and The mixture of molecular sieves in dioxane (2mL) was degassed and purged three times with _N2 . The mixture was then stirred at 110°C under _N2 atmosphere for 16hr. After completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water (FA)-ACN]; B%: 55%-70%, 26 minutes) to give the title compound (170mg, 33% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.81 (s, 1H), 6.93-6.83 (m, 2H), 6.75-6.68 (m, 1H), 3.90 (d, J = 11.2Hz, 2H), 3.54 (s, 3H), 2.81 (d, J = 6.4Hz, 2H), 2.63 (d, J = 3. 2Hz, 1H), 2.57 (s, 3H), 1.65-1.65 (m, 1H), 1.69 (d, J = 10.4Hz, 3H), 1.37 (s, 9H), 1.04-0.95 (m, 2H). LC-MS(ESI ⁺ )m/z 374.2(M+H) ⁺ .

Step 2-4-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo [4-(2-Benzimidazol-4-yl)-methyl-amino]methyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-[[methyl-(3-methyl-2-oxo-1H-benzimidazol-4-yl)amino]methyl]piperidine-1-carboxylate (170 mg, 454 μmol) in THF (1 mL) was added t-BuOK (92.0 mg, 817 μmol) dropwise at -10°C. After addition, the mixture was stirred at this temperature for 30 minutes, and then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (225 mg, 590 μmol, Intermediate G) was added dropwise in THF (1 mL) at -10°C. The resulting mixture was stirred at -10°C for 12 hours. Upon completion, the mixture was quenched by NH ₄ Cl (2 mL), diluted with H ₂ O (8 mL), and extracted with EA (2×5 mL). The organic layer was then washed with brine (2 x 3 mL), dried _over anhydrous _Na2SO4 and concentrated in vacuo to give the title compound as a red oil (274 mg, 100% yield). LC-MS (ESI ⁺ ) m/z 606.2 (M+H) ⁺ .

Step 3-3-[3-methyl-4-[methyl(4-piperidinylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidin- 2,6-Dione

To a solution of tert-butyl 4-[[[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzoimidazol-4-yl]-methyl-amino]methyl]piperidine-1-carboxylate (270 mg, 446 μmol) in TfOH (0.3 mL) was added TFA (3.70 g, 32.4 mmol, 2.4 mL). The mixture was then stirred at 70 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (170 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 386.2 (M+H) ⁺ .

Step 4-4-[[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-methyl- tert-Butyl]amino]methyl]piperidine-1-carboxylate

To a solution of 3-[3-methyl-4-[methyl(4-piperidinylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (170 mg, 441 μmol) in DCM (1 mL) was added TEA (134 mg, 1.32 mmol, 185 μL) and tert-butyl butyloxycarbonyl (106 mg, 485 μmol, 112 μL). The mixture was stirred at 25 °C for 3 hr. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 2/1) to give the title compound (200 mg, 87% yield) as a yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.24 (s, 1H), 7.03-6.97 (m, 1H), 6.94-6.88 (m, 1H), 6.58 (d, J = 8Hz, 1H), 5.23 (dd, J = 5.2, 12.4Hz, 1H), 4.13 (d, J = 7.2Hz, 1H), 3.75 (s ,3H),2.97-2.71(m,6H),2.66(s,3H),2.27-2.19(m,1H),2.05(s,1H),1.75(d,J＝12Hz,2H),1.46(s,9H),1.30-1.24(m,2H),1.17(s,2H). LC-MS(ESI ⁺ )m/z 486.0(M+H) ⁺ .

Step 5-3-[3-methyl-4-[methyl(4-piperidinylmethyl)amino]-2-oxo-benzimidazol-1-yl]piperidin- 2,6-Dione

To a solution of tert-butyl 4-[[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-methyl-amino]methyl]piperidine-1-carboxylate (90.0 mg, 185 μmol) in DCM (0.5 mL) was added TFA (578 mg, 5.06 mmol, 375 μL). The mixture was stirred at 25 °C for 2 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (71 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 386.3 (M+H) ⁺ .

3-[3-methyl-4-[methyl-[[1-(4-piperidinyl)-4-piperidinyl]methyl]amino]-2-oxo-benzimidazole- 1-yl]piperidine-2,6-dione (Intermediate HS)

Step 1-4-[4-[[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-methyl tert-Butyl-amino]methyl]-1-piperidinyl]piperidine-1-carboxylate

To a solution of 3-[3-methyl-4-[methyl(4-piperidinylmethyl)amino]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (71 mg, 184 μmol, Intermediate HR) and tert-butyl 4-oxopiperidine-1-carboxylate (367 mg, 1.84 mmol, CAS#79009-07-3) in THF (3 mL) was added KOAc (362 mg, 3.68 mmol) slowly at 0° C. Then NaBH(OAc) ₃ (390 mg, 1.84 mmol) was added dropwise at 0° C. and the resulting mixture was stirred at 0° C. for 12 hr. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 12%-42%, 10min) to give the title compound (70.0mg, 67% yield) as a white solid. ^1H NMR (400MHz, CDCl ₃ )δ8.04(s,1H),7.03-6.98(m,1H),6.90(d,J＝8.0Hz,1H),6.59(d,J＝8.0Hz,1H),5.26-5.18(m,1H),4.33-4.20(m,2H),3.73(s,3H),3.52-3.33(m,3H ),3.25-3.18(m,1H),3.00-2.93(m,2H),2.69-2.66(m,5H),2.28-2.22(m,1H),2.15-2.08(m,2H),2.06-1.93(m,5H),1.66-1.58(m,6H),1.45(s,9 H). LC-MS(ESI ⁺ )m/z569.3(M+H) ⁺ .

Step 2-3-[3-methyl-4-[methyl-[[1-(4-piperidinyl)-4-piperidinyl]methyl]amino]-2-oxo-benzene [[(-imidazol-1-yl]piperidin-2,6-dione]]

To a solution of tert-butyl 4-[4-[[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-methyl-amino]methyl]-1-piperidinyl]piperidine-1-carboxylate (30.0 mg, 52.8 μmol) in DCM (0.5 mL) was added TFA (770 mg, 6.75 mmol, 0.5 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (24 mg, 98% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 469.3 (M+H) ⁺ .

6-(2-Oxoethoxy)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (Intermediate HT)

To a solution of tert-butyl 6-(2-hydroxyethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 971 μmol, synthesized via step 1-2 of Intermediate FE) in DCM (3 mL) was added DMP (535 mg, 1.26 mmol). The mixture was stirred at 25 °C for 2 hr. Upon completion, the reaction mixture was quenched with H ₂ O (0.1 mL) at 25 °C, and then diluted with H ₂ O (5 mL) and extracted with EA (10 mL×3). The combined organic layers were washed with brine (10 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (248 mg, 99% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.53-9.51(m,1H),4.04-3.98(m,1H),3.76(d,J＝18.6Hz,4H),3.30(s,2H),2.43-2.34(m,2H),2.00-1.91(m,2H),1.33(s,9H) .

3-[5-[1-[2-(2-azaspiro[3.3]hept-6-yloxy)ethyl]-4-piperidinyl]-3-methyl-2-oxo-benzene [(1-imidazol-1-yl]piperidine-2,6-dione (Intermediate HU)

Step 1-6-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]- 1-Piperidinyl]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl 6-(2-oxoethoxy)-2-azaspiro[3.3]heptane-2-carboxylate (240 mg, 940. μmol, intermediate HT), 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (284 mg, 752 μmol, HCl, intermediate DB) in THF (0.5 mL), DMF (0.5 mL) was added KOAc (923 mg, 9.40 mmol) and NaBH(OAc) ₃ (398 mg, 1.88 mmol). The mixture was stirred at 0° C. for 2 hr. After completion, the reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 23%-53%, 9 min) to give the title compound (100 mg, 12% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 583.0 (M+H) ⁺ .

Step 2-3-[5-[1-[2-(2-azaspiro[3.3]hept-6-yloxy)ethyl]-4-piperidinyl]-3-methyl-2- [Oxo-benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 6-[2-[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]ethoxy]-2-azaspiro[3.3]heptane-2-carboxylate (80 mg, 137 μmol) in DCM (0.4 mL) was added TFA (616 mg, 5.40 mmol). The mixture was stirred at 25 °C for 0.2 hr. Upon completion, the reaction mixture was concentrated under reduced pressure to give the title compound (65 mg, 79% yield, TFA) as a yellow oil. LC-MS (ESI ⁺ ) m/z 482.7 (M+H) ⁺ .

1-[4-[4-(2-aminoethyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate HV)

Step 1 - N-[2-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]benzene tert-Butyl]-4-piperidinyl]ethyl]carbamate

A mixture of 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (500 mg, 1.28 mmol, Intermediate DS), tert-butyl N-[2-(4-piperidinyl)ethyl]carbamate (293 mg, 1.28 mmol, CAS#165528-81-4), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (165 mg, 192 μmol, CAS#1435347-24-2), and _Cs2CO3 (837 mg, 2.57 mmol) in _dioxane (5 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100 °C under _N2 atmosphere for 16 hr. After completion, the reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and the filtrate concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (200 mg, 29% yield) as a light yellow solid. LC-MS (ESI ⁺ ) m/z 537.4 (M+H) ⁺ .

Step 2-1-[4-[4-(2-aminoethyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]ethyl]carbamate (50 mg, 93.1 μmol) in TFA (0.8 mL) and TfOH (0.1 mL). The mixture was stirred at 70 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo, and DMSO (1 mL) and DIEA were added until pH = 8. The mixture was then diluted with water and lyophilized to give the title compound (30 mg, 17% yield) as a light yellow solid. LC-MS (ESI ⁺ ) m/z 317.0 (M+H) ⁺ .

Spiro[2.4]heptyl-7-amine (Intermediate HW)

Step 1 - Spiro[2.4]heptan-7-ol

To a solution of spiro[2.4]heptan-7-one (4.50 g, 40.8 mmol, CAS#5771-32-4) in EtOH (40 mL) was added _NaBH4 (3.91 g, 103 mmol) at 0°C. The reaction was then stirred at 25°C for 2 hr. Upon completion, the reaction was quenched with _NH4Cl (10 mL). The mixture was diluted with EA (400 mL), washed with water (200 mL x 3), dried over _Na2SO4 and filtered. _The filtrate was concentrated in vacuo to give the title compound (2.91 g, 63% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ4.28 (d, J = 4.4 Hz, 1H), 3.51-3.45 (m, 1H), 1.93-1.83 (m, 1H), 1.81-1.70 (m, 2H), 1.66-1.49 (m, 2H), 1.43-1.33 (m, 1H), 0.77- 0.69(m,1H),0.43-0.29(m,3H).

Step 2-2-Spiro[2.4]hept-7-ylisoindoline-1,3-dione

To a _solution of spiro[2.4]heptan-7-ol (2.40 g, 21.4 mmol), isoindoline-1,3-dione (3.78 g, 25.6 mmol, CAS#85-41-6) and PPh ₃ (8.42 g, 32.0 mmol) in THF (60 mL) was added DIAD (6.49 g, 32.0 mmol) at 25° C. under N 2. The reaction was stirred at 60° C. for 16 hr. Upon completion, ice water (100 mL) was added to the reaction. The mixture was extracted with EA (200 mL) and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=20/1 to 10/1) to give the title compound (1.7 g, 32% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.83 (s, 4H), 4.32 (t, J = 8.0Hz, 1H), 2.26-2.10 (m, 3H), 2.02-1.93 (m, 1H), 1.80-1.67 (m, 1H), 1.49-1.34 (m, 1H), 0.63-0.54 (m,1H),0.51-0.41(m,2H),0.32-0.24(m,1H).

Step 3 - Spiro[2.4]heptyl-7-amine

To a solution of 2-spiro[2.4]hept-7-ylisoindoline-1,3-dione (1.4 g, 5.8 mmol) in THF ₍ 30 mL) was added _NH2NH2.H2O (1.66 g, 33.1 mmol). The reaction was stirred at 60 °C for ₃ hr. Upon completion, the reaction was diluted with THF (30 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound (550 mg, 85% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ2.84(t,J=5.6Hz,1H),2.13-2.02(m,1H),1.88-1.78(m,2H),1.76-1.64(m,1H),1.48-1.42(m,2H),1.28(s,2H),0.64-0.57(m ,1H),0.49-0.29(m,3H).

4-[(6-chloro-7-oxo-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl- Benzenesulfonyl chloride (intermediate HX)

Step 1 - 5-Bromo-2-chloro-N-spiro[2.4]hept-7-yl-pyrimidin-4-amine

To a solution of 5-bromo-2,4-dichloro-pyrimidine (983 mg, 4.32 mmol, CAS# 36082-50-5) and TEA (567 mg, 5.61 mmol) in ACN (15 mL) at 0°C was added spiro[2.4]hept- ₇ -amine (480 mg, 4.32 mmol, intermediate HW). The reaction was then stirred at 25°C for 16 hr. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (50 mL x 2), dried over _Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 1/0 to 30/1) to give the title compound (505 mg, 38% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 303.7 (M+H) ⁺ .

Step 2-N2-(4-Benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-spiro[2.4]hept-7-yl-pyrimidine-2,4- Diamine

To _a solution of 5-bromo-2-chloro-N-spiro[2.4]hept-7-yl-pyrimidin-4-amine (450 mg, 1.49 mmol) and 4-benzylsulfanyl-2-methyl-aniline (375 mg, 1.64 mmol, intermediate DE) in IPA (10 mL) was added TFA (3.39 g, 29.7 mmol) under N. The reaction was stirred at 80 °C under _N for 16 hr. Upon completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (70 mL) and concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (400 mg, 54% yield) as a red solid. LC-MS (ESI ⁺ ) m/z 496.9 (M+H) ⁺ .

Step 3-(E)-3-[2-(4-Benzylthio-2-methyl-phenylamino)-4-(spiro[2.4]hept-7-ylamino)pyrimidine [5-pyridin-1-yl]prop-2-enoic acid methyl ester

To a mixture of N2-(4-benzylsulfanyl-2-methyl-phenyl)-5-bromo-N4-spiro[2.4]hept-7-yl-pyrimidine-2,4-diamine (340 mg, 686 μmol), TEA (208 mg, 2.06 mmol) and Pd(PPh ₃ ) ₄ (158 mg, 137 μmol) in DMF (3.5 mL) was added prop-2-enoic acid methyl ester (0.54 g, 6.27 mmol). The reaction was then stirred at 90 °C under N ₂ for 16 hr. Upon completion, the reaction was diluted with water (50 mL) and extracted with EA (70 mL×2). The organic layer was washed with water (50 mL×3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (200 mg, 58% yield) as brown oil. LC-MS (ESI ⁺ ) m/z 501.3 (M+H) ⁺ .

Step 4-2-(4-Benzylthio-2-methyl-phenylamino)-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidine Pyridin-7-one

To a solution of (E)-3-[2-(4-benzylsulfanyl-2-methyl-phenylamino)-4-(spiro[2.4]hept-7-ylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester (180 mg, 359 μmol) in DMF (3 mL) was added t-BuOK (121 mg, 1.08 mmol) at 25 °C and stirred for 0.5 hr. Subsequently, the reactant was stirred at 120 °C for 2 hr. Upon completion, the reactant was diluted with EA (40 mL). The organic layer was washed with water (30 mL×3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 1/1) to give the title compound (80 mg, 47% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 469.6 (M+H) ⁺ .

Step 5-4-[(6-chloro-7-oxo-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-2-yl)amino]- 3-Methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (80.0 mg, 170 μmol) in HOAc (0.1 mL) and ACN (1 mL) was added NCS (91.1 mg, 682 μmol) and H ₂ O (30.7 μg, 1.71 μmol) in the dark. The reaction was stirred at 25 °C in the dark for 0.5 hr. After completion, the reaction was diluted with EA (50 mL). The organic layer was washed with water (50 mL), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5/1 to 2/1) to give the title compound (60 mg, 73% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 479.0(M+H) ⁺ .

tert-Butyl 4-(4-piperidinyloxymethyl)piperidine-1-carboxylate (Intermediate HY)

Step 1-4-(4-pyridyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol, CAS#123855-51-6), pyridin-4-ol (4.42 g, 46.5 mmol, CAS#626-64-2), _PPh3 (25.0 g, 93.0 mmol), DIAD (19.0 g, 93.0 mmol, 18.0 mL) in THF (50 mL) was degassed and purged with _N2 three times, and then the mixture was stirred at 25 °C under _N2 atmosphere for 16 hr. Upon completion, the mixture was diluted with _H2O (50 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 30 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (4.9 g, 37% yield) as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 6.0 Hz, 2H), 6.82 (d, J = 6.0 Hz, 2H), 4.18 (d, J = 4.0 Hz, 2H), 3.87 (d, J = 6.4 Hz, 2H), 2.76 (t, J = 12.4 Hz, 2H), 2.09-1.90 (m, 1H), 1.82 (d, J = 12.8 Hz, 2H), 1.48 (s, 9H), 1.35-1.23 (m, 2H). LC-MS (ESI ⁺ ) m/z 293.3 (M+H) ⁺ .

Step 2-4-(4-piperidinyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4-(4-pyridyloxymethyl)piperidine-1-carboxylate (2 g, 6.84 mmol), _PtO2 (1.55 g, 6.84 mmol), HOAc (8.40 g, 140 mmol, 8.00 mL) in EtOH (20 mL) was degassed and purged with _H2 three times. The mixture was then stirred at 40 °C under _H2 atmosphere for 16 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (2.00 g, 82% yield, HOAc salt) as a white oil. ² .34-2.19(m,1H),1.88-1.76(m,1H),1.63(d,J＝12.0Hz,3H) _, 1.49-1.41(m,2H),1.38(s,9H),1.09-0.93(m,3H). LC-MS(ESI ⁺ )m/z 299.1(M+H) ⁺ .

3-[3-methyl-2-oxo-4-[4-(4-piperidinylmethoxy)-1-piperidinyl]benzimidazol-1-yl]piperidin-2-yl 6-Diketone (Intermediate HZ)

Step 1-4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]oxymethyl]piperidinyl- 1-tert-Butyl formate

tert-Butyl 4-(4-piperidinyloxymethyl)piperidine-1-carboxylate (50 mg, 168 μmol, Intermediate HY), 4-bromo-3-methyl-1H-benzimidazol-2-one (150 mg, 661 μmol, synthesized via Steps 1-3 of Intermediate H), Cs ₂ CO ₃ (1.35 g, 4.13 mmol), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; dichloropalladium (71.0 mg, 83.0 μmol) and The mixture of molecular sieves in dioxane (1 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 ° C under N ₂ atmosphere for 12 hr. After completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (FA)-ACN]; B%: 65%-95%, 10 minutes) to give the title compound (70 mg, 9% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 445.3 (M+H) ⁺ .

Step 2-4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2- [Oxo-benzoimidazol-4-yl]-4-piperidinyl]oxymethyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]oxymethyl]piperidine-1-carboxylate (100 mg, 225 μmol) in THF (1 mL) was added t-BuOK (46 mg, 405 μmol) and [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (112 mg, 293 μmol, intermediate CY). The mixture was stirred at -10 °C for 6 hr. Upon completion, the mixture was quenched with _NH4Cl (1 mL), diluted with _H2O (8 mL), and extracted with EA (2 x 5 mL). The organic layer was then washed with brine (2 x 3 mL), dried _over anhydrous _Na2SO4 , and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate=0:1) to give the title compound (130 mg, 77% yield) as a red oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ7.21 (d, J=8.8 Hz, 2H), 6.95-6.88 (m, 2H), 6.85 (d, J=8.8 Hz, 2H), 6.75 (d, J=5.6 Hz, 1H), 5.53-5.46 (m, 1H), 4.86-4.70 (m, 2H), 3.98-3.89 (m, 2H), 3.72 (s, 3H), 3.71 (d, J=1.6 Hz, 1H),3.62(s,3H),3.12-3.00(m,2H),2.84-2.69(m,5H),2.06-1.98(m,3H),1.88-1.81(m,1H),1.74-1.60(m,4H),1.59-1.51(m,1H),1.39(s,9H) ,1.24(s,3H),1.09-0.99(m,2H). LC-MS(ESI ⁺ )m/z 676.4(M+H) ⁺ .

Step 3-3-[3-methyl-2-oxo-4-[4-(4-piperidinylmethoxy)-1-piperidinyl]benzimidazol-1-yl] Piperidine-2,6-dione

To a solution of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]oxymethyl]piperidine-1-carboxylate (30 mg, 44.4 μmol) in TFA (0.8 mL) was added TfOH (170 mg, 1.13 mmol, 100 μL). The mixture was stirred at 70 °C for 2 hr. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA=0:1) to give the title compound (20 mg, 97% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 456.1 (M+H) ⁺ .

N-[2-(4-Formylcyclohexyloxy)ethyl]-N-methyl-carbamic acid tert-butyl ester (Intermediate IA)

Step 1 - N-[2-[4-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclohexyloxy]ethyl]-N-methyl- Tert-Butyl Carbamate

To a solution of tert-butyl N-[2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl]carbamate (400 mg, 781 μmol, synthesized via step 1-6 of Intermediate DP) in THF (4 mL) was added NaH (93.8 mg, 2.34 mmol, 60% dispersion in mineral oil) and MeI (389 μL, 6.25 mmol) at 0°C, and then the mixture was stirred at 25°C for 10 hr. After completion, the mixture was quenched with sat. NH ₄ Cl (3 mL), then washed with water (50 mL) and extracted with EA (50 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=100:3 to 20:1) to give the title compound (300 mg, 73% yield) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ7.67-7.65(m,4H),7.47-7.33(m,6H),3.57-3.56(m,2H),3.47-3.45(m,2H),3.37(s,2H),3.19-3.14(m,1H),2.93(s,3H),2. 09-2.00(m,2H),1.85-1.82(m,2H),1.58-1.51(m,1H),1.47(s,9H),1.24-1.16(m,2H),1.06(s,9H),1.03-0.94(m,2H).

Step 2 - N-[2-[4-(Hydroxymethyl)cyclohexyloxy]ethyl]-N-methyl-carbamic acid tert-butyl ester

To a solution of tert-butyl N-[2-[4-[[tert-butyl(diphenyl)silanyl]oxymethyl]cyclohexyloxy]ethyl]-N-methyl-carbamate (300 mg, 570 μmol) in THF (3 mL) was added TBAF (1 M, 855 μL), and the mixture was then stirred at 25° C. for 2 hr. Upon completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=20:1 to 2:1) to give the title compound (150 mg, 91% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ3.58(s,2H),3.46-3.45(m,2H),3.36-3.35(m,2H),3.25-3.15(m,1H),2.92(s,3H),2.07-2.04(m,2H),1.85-1.82(m,2H),1.6 4-1.53(m,1H),1.46(s,9H),1.27-1.17(m,2H),1.05-0.91(m,2H).

Step 3 - N-[2-(4-Formylcyclohexyloxy)ethyl]-N-methyl-carbamic acid tert-butyl ester

To a solution of tert-butyl N-[2-[4-(hydroxymethyl)cyclohexyloxy]ethyl]-N-methyl-carbamate (50.0 mg, 174 μmol) in DCM (1 mL) was added DMP (110 mg, 261 μmol) at 0°C, and then the mixture was stirred at 25°C for 2 hr. After completion, the mixture was quenched with sodium thiosulfate pentahydrate (5 mL) and NaHCO ₃ (5 mL), and then extracted with DCM (10 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , and then concentrated in vacuo to give the title compound (30.0 mg, 60% yield) as a yellow oil.

3-[3-methyl-5-[1-[[4-[2-(methylamino)ethoxy]cyclohexyl]methyl]-4-piperidinyl]-2-oxo-benzene [[(1-((((((((((((((((((((((((piperidinazole-1-ylpiperidine-2,6-dione

Step 1-N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5- tert-butyl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]-N-methyl-carbamate

To a solution of 3-[3-methyl-2-oxo-5-(4-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (38.4 mg, 84.1 μmol, TFA, intermediate DB) in THF (1 mL) was added TEA (14.6 μL, 105 μmol). Then tert-butyl N-[2-(4-formylcyclohexyloxy)ethyl]-N-methyl-carbamate (30.0 mg, 105 μmol, intermediate IA) and HOAc (6.01 μL, 105 μmol) were added, and the mixture was stirred at -10 °C for 0.5 hr. Then, NaBH(OAc) ₃ (33.4 mg, 158 μmol) was added, and the mixture was stirred at -10 °C for 1.5 hr. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 15%-45%, 8 min) to give the title compound (10.0 mg, 16% yield) as a colorless gum. LC-MS (ESI ⁺ ) m/z 612.4 (M+H) ⁺ .

Step 2-3-[3-methyl-5-[1-[[4-[2-(methylamino)ethoxy]cyclohexyl]methyl]-4-piperidinyl]-2- [Oxo-benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[2-[4-[[4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-1-piperidinyl]methyl]cyclohexyloxy]ethyl]-N-methyl-carbamate (10.0 mg, 16.3 μmol) in DCM (0.5 mL) was added TFA (0.2 mL, 2.70 mmol), and the mixture was then stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (10.0 mg, 97% yield, TFA) as a colorless oil. LC-MS (ESI ⁺ ) m/z 512.2 (M+H) ⁺ .

tert-Butyl N-[5-[(2-chloroacetyl)amino]pentyl]carbamate (Intermediate IC)

To a solution of tert-butyl N-(5-aminopentyl)carbamate (500 mg, 2.47 mmol, 514 μl, CAS#51644-96-3) in THF (5 mL) was added 2-chloroacetyl chloride (418 mg, 3.71 mmol, 29.0 μL, CAS#79-04-9) and the mixture was stirred at 25 °C for 1 hour. Upon completion, the mixture was concentrated in vacuo to give the title compound (500 mg, 72% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 178.9 (M+H) ⁺ .

N-(5-aminopentyl)-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide (Intermediate ID)

Step 1 - N-[5-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]pentyl]amino tert-Butyl formate

To a solution of tert-butyl N-[5-[(2-chloroacetyl)amino]pentyl]carbamate (500 mg, 1.79 mmol, Intermediate IC) and 4-(2,6-dibenzyloxy-3-pyridinyl)phenol (206 mg, 538 μmol, Intermediate IE) in THF (5 mL) was added NaOH (322 mg, 8.07 mmol). The mixture was then stirred at 25 °C for 1 hr. Upon completion, the mixture was diluted with _H2O (0.5 mL) and then concentrated in vacuo to give the title compound (183 mg, 16% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.05(t,J＝5.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.50-7.29(m,12H),6.97(d,J＝8.4Hz,2H),6.79-6.71(m,1H),6.53(d,J＝8.0Hz,1 H),5.38(d,J=12.8Hz,4H),4.47(s,2H),3.13-3.08(m,2H),2.93-2.83(m,4H),2.07(s,2H),1.36(s,9H),1.25-1.19(m,2H). LC-MS(ESI ⁺ )m/z 626.3(M+H) ⁺ .

Step 2-N-[5-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]pentyl]aminomethoxy Tert-butyl ester

To a solution of tert-butyl N-[5-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]pentyl]carbamate (173 mg, 276 μmol) in THF (2.00 mL) was added Pd/C (2.00 mg, 2.76 μmol, 10 wt%). The mixture was then stirred at 25 °C under _H2 for 1 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (48.0 mg, 38% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 347.9 (M-100) ⁺ .

Step 3 - N-(5-aminopentyl)-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide

To a solution of tert-butyl N-[5-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]pentyl]carbamate (48.0 mg, 107 μmol) in TFA (1 mL) and DCM (2 mL). The mixture was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated in vacuo to give the title compound as a colorless oily liquid (37.0 mg, 74% yield, TFA). LC-MS (ESI ⁺ ) m/z 347.9 (M+H) ⁺ .

4-(2,6-Bis(benzyloxy)pyridin-3-yl)phenol (Intermediate IE)

A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (9.50 g, 22.8 mmol, CAS#2152673-80-6), 4-bromophenol (3.94 g, 22.8 mmol, CAS _# 106-41-2) _{, K2CO3 (} 9.44 g, 68.3 mmol) and Pd(dppf) _Cl2.CH2Cl2 (1.86 g, 2.28 mmol) in _dioxane (150 mL) and _H2O (30 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 80 °C under _N2 atmosphere for 12 hr. Upon completion, the reaction mixture was diluted with _H2O (200 mL) and extracted with EA (200 mL x 2). The combined organic layers were washed with aqueous NaCl solution (200 mL x 2), dried _{over Na2SO4} , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate = 10/1 to 5/1) to give the title compound (7 g, 79% yield) as an off-white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.45 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.49-7.24 (m, 12H), 6.78 (d, J = 8.4 Hz, 2H), 6.51 (d, J = 8.0 Hz, 1H), 5.38 (d, J = 13.2 Hz, 4H); LC-MS (ESI ⁺ ) m/z 384.2 (M+H) ⁺ .

Tert-butyl N-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethyl]carbamate (Intermediate IF)

To a solution of tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (500 mg, 2.45 mmol, CAS#127828-22-2) in DCM (5 mL) was added TEA (743 mg, 7.34 mmol). 2-Chloroacetyl chloride (331.75 mg, 2.94 mmol, CAS#79-04-9) in DCM (3 mL) was then added to the mixture at 0 °C. The reaction was stirred at 25 °C for 1 hr. Upon completion, the mixture was diluted with DCM (60 _mL ) and washed with water (50 mL x 3). The organic layer was dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to give the title compound (610 mg, 88% yield) as a yellow oil.

N-[2-(2-aminoethoxy)ethyl]-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide (intermediate IG)

Step 1 - N-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy tert-Butyl]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethyl]carbamate (246 mg, 876 μmol, Intermediate IF) and 4-(2,6-benzhydryloxy-3-pyridinyl)phenol (120 mg, 312 μmol, Intermediate IE) in DMF (4 mL) was added Cs ₂ CO ₃ (305 mg, 938 μmol). The reaction was then stirred at 50 °C for 4 hr. Upon completion, the mixture was diluted with EA (50 mL) and washed with water (30 mL×3). The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1). Subsequently, the crude product was further purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 66%-96%, 10min) to give the title compound (196mg, 99% yield) as a colorless oil. ^1H NMR (400MHz, DMSO-d ₆ )δ8.08(m,J＝5.6Hz,1H),7.69(d,J＝8.0Hz,1H),7.51-7.46(m,2H),7.45-7.41(m,2H),7.40-7.23(m,8H),6.97(d,J＝8.8Hz,2H),6.81-6.69(m,1H),6.5 2(d,J＝8.0Hz,1H),5.39(s,2H),5.36(s,2H),4.49(s,2H),3.45-3.39(m,2H),3.36(t,J＝6.0Hz,2H),3.27(s,1H),3.05(m,J＝5.6Hz,2H),1.42-1.42( m,1H),1.35(s,9H).

Step 2-N-[2-[2-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]ethoxy] tert-Butyl]ethylcarbamate

To a solution of tert-butyl N-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy]ethyl]carbamate (100 mg, 159 μmol) in MeOH (4 _mL ) was added Pd/C (50 mg, 159 μmol, 10 wt %) under N atmosphere. The suspension was degassed and purged with _H three times. The mixture was then stirred at 25 °C under _H (15 Psi) atmosphere for 2 hr. Upon completion, the mixture was diluted with MeOH (10 mL), filtered and the filtrate was concentrated in vacuo to give the title compound (59 mg, 82% yield) as a colorless solid. LC-MS (ESI ⁺ ) m/z 350.0 (M+H) ⁺ .

Step 3 - N-[2-(2-aminoethoxy)ethyl]-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl amine

A mixture of tert-butyl N-[2-[2-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]ethoxy]ethyl]carbamate (59 mg, 131 μmol) in HCl/EtOAc (4M, 4 mL) was stirred at 25°C for 0.5 hr. After completion, the mixture was concentrated in vacuo to give the title compound (45 mg, 98% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 350.0 (M+H) ⁺ .

tert-Butyl N-[2-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethoxy]ethyl]carbamate (intermediate IH)

To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (500 mg, 2.01 mmol, CAS#153086-78-3) in DCM (3 mL) was added TEA (840 μL, 6.04 mmol). Then a solution of 2-chloroacetyl chloride (192 μL, 2.42 mmol, CAS#79-04-9) in DCM (2 mL) was added dropwise at 0°C, and the mixture was stirred at 25°C for 1 hr. Upon completion, the mixture was diluted with DCM (50 mL) and washed with water (40 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and then concentrated in vacuo to give the title compound (550 mg, 84% yield) as a yellow oil.

N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy] Acetamide (Intermediate II)

Step 1 - N-[2-[2-[2-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino] tert-Butyl]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-[2-[(2-chloroacetyl)amino]ethoxy]ethoxy]ethyl]carbamate (474 mg, 1.46 mmol, Intermediate IH) and 4-(2,6-benzhydryloxy-3-pyridinyl)phenol (280 mg, 730 μmol, Intermediate IE) in DMF (5 mL) was added Cs ₂ CO ₃ (713 mg, 2.19 mmol), and then the mixture was stirred at 50° C. for 2 hours. After completion, the mixture was filtered and the filtrate was diluted with EA (40 mL) and washed with water (30 mL×3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ and then concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=20:1 to 1:2) to give the title compound (480 mg, 97% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.24(s,1H),8.07(t,J＝5.6Hz,1H),7.70(d,J＝8.0Hz,1H),7.49(d,J＝8.8Hz,2H),7.46-7.41(m,2H),7.40-7.32(m,7H),6.97( d,J＝8.8Hz,2H),6.74(s,1H),6.53(d, J＝8.0Hz,1H),5.75(s,1H),5.38(d,J＝13.6Hz,4H),4.49(s,2H),4.06(s,1H),3.49-3.47(m,4H),3.44-3.43(m,2H),3.37-3.36(m,2H),3.06-3.04(m ,2H),1.36(s,9H). LC-MS(ESI ⁺ )m/z 672.5(M+H) ⁺ .

Step 2-N-[2-[2-[2-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]ethoxy tert-Butyl]ethoxy]ethyl]carbamate

To a solution of tert _-butyl N-[2-[2-[2-[[2-[4-(2,6-benzyloxy-3-pyridyl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate (150 mg, 223 μmol) in MeOH (1 mL) was added Pd/C (50.0 mg, 10 wt%) under N atmosphere. The mixture was then degassed and filled with _H three times and then stirred at 25 °C under _H (15 psi) for 2 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg, 90% yield) as a white gum. LC-MS (ESI ⁺ ) m/z 494.0 (M+H) ⁺ .

Step 3 - N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2-[4-(2,6-dioxo-3-piperidinyl)benzene oxy]acetamide

A solution of tert-butyl N-[2-[2-[2-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]ethoxy]ethoxy]ethyl]carbamate (50.0 mg, 101 μmol) in HCl/dioxane (1 mL) was stirred at 25° C. for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound as a white solid (40.0 mg, 91% yield, HCl). LC-MS (ESI ⁺ ) m/z 394.0 (M+H) ⁺ .

3-[3-methyl-2-oxo-5-[4-(4-piperidinyloxy)-1-piperidinyl]benzimidazol-1-yl]piperidin-2,6- Diketone (Intermediate IJ)

Step 1-4-[[1-[3-(Methylamino)-4-nitro-phenyl]-4-piperidinyl]oxy]piperidine-1-carboxylic acid tert-butyl ester

A mixture of 5-fluoro-N-methyl-2-nitro-aniline (498 mg, 2.93 mmol, CAS#120381-42-2), TEA (889 mg, 8.79 mmol, 1.22 mL) and tert-butyl 4-(4-piperidinyloxy)piperidine- ₁ -carboxylate (1.00 g, 3.52 mmol, CAS#845305-83-1) in DMSO (12 mL) was stirred at 50 °C for 2 hr. After completion, the reaction mixture was diluted with EA (90 mL) and washed with water (30 mL x 3). The organic layer was dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by column chromatography ( _SiO2 , PE:EA=3:1 to 1:1) to give the title compound (1.05 g, 82% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.35(d,J＝4.8Hz,1H),7.88(d,J＝9.6Hz,1H),6.47-6.36(m,1H),5.92(d,J＝2.4Hz,1H),3.82-3.69(m,3H),3.68-3.59(m,3H),3. 27-3.15(m,2H),3.09-2.96(m,2H),2.93(d,J＝4.8Hz,3H),1.92-1.82(m,2H),1.79-1.69(m,2H),1.51-1.42(m,2H),1.39(s,9H),1.36-1.27(m,2H)

Step 2-4-[[1-[4-amino-3-(methylamino)phenyl]-4-piperidinyl]oxy]piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-[[1-[3-(methylamino)-4-nitro-phenyl]-4-piperidinyl]oxy]piperidine-1-carboxylate (1 g, 2.30 mmol) in THF (20 mL) under Ar was added Pd/C (500 mg, 2.30 mmol, 10 wt%). The suspension was degassed in vacuo and purged with _H2 several times. The mixture was then stirred under _H2 (15 psi) at 25 °C for 5 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (853 mg, 91% yield) as a yellow oil. ¹ H NMR(400MHz,DMSO-d ₆ )δ6.40(d,J＝8.0Hz,1H),6.08-5.97(m,2H),4.55-4.47(m,1H),3.98(s,2H),3.68-3.58(m,3H),3.54-3.46(m,1H),3.28-3.20(m,2H),3.00(s,2H),2.68(d,J＝5.2Hz,3H),2.67-2.60(m,2H),1.92-1.82(m,2H),1.81-1.71(m,2H),1.57-1.47(m,2H),1.39(s,9H),1.35-1.25(m,2H)。

Step 3-4-[[1-(3-methyl-2-oxo-1H-benzimidazol-5-yl)-4-piperidinyl]oxy]piperidin-1-carboxylate Tert-butyl ester

A mixture of tert-butyl 4-[[1-[4-amino-3-(methylamino)phenyl]-4-piperidinyl]oxy]piperidine-1-carboxylate (800 mg, 1.98 mmol) and CDI (480 mg, 2.97 mmol) in ACN (10 mL) was stirred at 80 °C for 4 hr. After completion, the reaction mixture was concentrated in vacuo to remove ACN (5 mL). The mixture was then added dropwise to water (80 mL) and filtered. The filter cake was dried in vacuo to give the title compound (680 mg, 79% yield) as a purple solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.48 (s, 1H), 6.79 (d, J = 8.4Hz, 1H), 6.73 (d, J = 1.6Hz, 1H), 6.59-6.55 (m, 1H), 3.68-3.53 (m, 4H), 3.42-3.35 (m, 2H), 3.23 (s, 3 H),3.01(t,J=9.6Hz,2H),2.86-2.73(m,2H),1.94-1.86(m,2H),1.80-1.72(m,2H),1.60-1.49(m,2H),1.39(s,9H),1.35-1.26(m,2H).

Step 4-4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2- [Oxo-benzoimidazol-5-yl]-4-piperidinyl]oxy]piperidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-5-yl)-4-piperidinyl]oxy]piperidine-1-carboxylate (600 mg, 1.39 mmol) and tBuOK (234 mg, 2.09 mmol) in THF (7 mL) was stirred at 0° C. for 0.5 hr. Then, a mixture of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (797 mg, 2.09 mmol, Intermediate G) in THF (5 mL) was added dropwise to the above mixture and the mixture was stirred at 0° C. for 0.5 hr. After completion, the reaction mixture was diluted with EA (80 mL) and the organic layer was washed with water (50 mL×3). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , PE:EA=1:1 to 1:3 to 0:1) to give the title compound (900 mg, 97% yield) as a green solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.20 (d, J=8.8 Hz, 2H), 6.88-6.82 (m, 3H), 6.80 (d, J=8.4 Hz, 1H), 6.59-6.53 (m, 1H), 5.47-5.38 (m, 1H), 4.85-4.73 (m, 2H), 3.74-3.71 (m, 3H), 3.68-3.56 (m, 4H), 3.46-3.38 (m, 2H) ,3.30(s,3H),3.09-2.97(m,3H),2.86-2.77(m,3H),2.73-2.63(m,1H),2.06-2.00(m,1H),1.95-1.87(m,2H),1.80-1.71(m,2H),1.62-1.51(m,2 H),1.39(s,9H),1.35-1.27(m,2H).

Step 5-3-[3-methyl-2-oxo-5-[4-(4-piperidinyloxy)-1-piperidinyl]benzimidazol-1-yl]piperidinyl Pyridine-2,6-dione

A mixture of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]oxy]piperidine-1-carboxylate (300 mg, 453 μmol) and TfOH (1.02 g, 6.80 mmol, 0.6 mL) in TFA (3 mL) was stirred at 70° C. for 2.5 hr. After completion, the reaction mixture was concentrated in vacuo to give the title compound as a red oil (251 mg, 99% yield, TFA). LC-MS (ESI ⁺ ) m/z 441.9 (M+H) ⁺ .

3-[5-[4-[[1-(3-aminopropyl)-4-piperidinyl]oxy]-1-piperidinyl]-3-methyl-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate IK)

Step 1-N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazole-5- tert-Butyl]-4-piperidinyl]oxy]-1-piperidinyl]propyl]carbamate

To a solution of 3-[3-methyl-2-oxo-5-[4-(4-piperidinyloxy)-1-piperidinyl]benzimidazol-1-yl]piperidine-2,6-dione (250 mg, 450 μmol, TFA, intermediate IJ), TEA (136 mg, 1.35 mmol) and HOAc (108 mg, 1.80 mmol) in DMF (2 mL) and THF (2 mL) was added tert-butyl N-(3-oxopropyl)carbamate (169 mg, 975 μmol, intermediate GM). The mixture was stirred at 25 °C for 0.5 hr. Subsequently, NaBH(OAc) ₃ (143 mg, 675 μmol) was added and the mixture was stirred at 25 °C for 1.5 hr. Upon completion, the reaction mixture was quenched with water (0.2 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex C18 250*50mm*10μm; mobile phase: [water( _NH4HCO3 )-ACN]; _B %: 20%-50%, 8 min) to give the title compound (140 mg, 51% yield) as a white solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ11.05 (s, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 6.79-6.74 (m, 1H), 6.65-6.60 (m, 1H), 5.39-5.16 (m, 1H), 3.58-3.51 (m, 1H), 3.44-3.39 (m, 3H), 3.30 (s, 3H) ,2.94-2.88(m,3H),2.86-2.77(m,3H),2.64-2.60(m,1H),2.24(t,J＝7.2Hz,3H),2.06-1.94(m,4H),1.94-1.85(m,3H),1.83-1.73(m,3H),1.54-1 .47(m,4H),1.37(s,9H).

Step 2-3-[5-[4-[[1-(3-aminopropyl)-4-piperidinyl]oxy]-1-piperidinyl]-3-methyl-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]oxy]-1-piperidinyl]propyl]carbamate (35.0 mg, 58.4 μmol) and TFA (359 mg, 3.15 mmol) in DCM (1 mL) was stirred at 25 °C for 1 hr. After completion, the reaction mixture was concentrated in vacuo to give the title compound (35.8 mg, 99% yield, TFA) as a colorless oil. LC-MS (ESI ⁺ ) m/z 498.9 (M+H) ⁺ .

tert-Butyl N-[2-[2-[2-(4-piperidinylmethoxy)ethoxy]ethoxy]ethyl]carbamate (intermediate IL)

Step 1 - tert-Butyl N-[2-[2-[2-(4-pyridylmethoxy)ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]carbamate (500 mg, 2.01 mmol, CAS#139115-92-7) in THF (5 mL) was degassed and purged with _N2 three times. Then NaH (160 mg, 4.01 mmol, 60% dispersion in mineral oil) was added to the mixture at 0°C and the mixture was stirred for 1 hour. Then 4-(bromomethyl)pyridine (345 mg, 2.01 mmol, CAS#54751-01-8) was added and the mixture was stirred at 25°C under _N2 atmosphere for 2 hr. After completion, the reaction mixture was stirred with _H2O (10 mL) at 25°C and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried _{over Na2SO4} , filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18 250*50mm*10μm; mobile phase: [water (ammonia hydroxide v/v)-ACN]; B%: 18%-48%, 8 min) to give the title compound (200 mg, 28% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 341.2 (M+1) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.58(d,J＝6.0Hz,2H),7.29(d,J＝6.0Hz,2H),5.01(s,1H),4.60(s,2H),3.73-3.68(m,4H),3.68-3.63(m,4H),3.55(t,J＝4.8Hz, 2H),3.32-3.31(m,2H),1.44(s,9H).

Step 2-tert-Butyl N-[2-[2-[2-(4-piperidinylmethoxy)ethoxy]ethoxy]ethyl]carbamate

To a solution of tert _-butyl N-[2-[2-[2-(4-pyridylmethoxy)ethoxy]ethoxy]ethyl]carbamate (170 mg, 499 μmol) in EtOH (5 mL) and AcOH (525 mg, 8.74 mmol) was added _PtO (113 mg, 499 μmol) under N atmosphere. The suspension was degassed and purged with _H three times. The mixture was stirred under _H (15 psi) at 40 °C for 16 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (150 mg, 86% yield) as a white solid. ¹ HNMR (400MHz, CDCl ₃ ) δ5.33-4.94(m,1H),3.65-3.58(m,8H),3.56-3.52(m,2H),3.44-3.29(m,6H),2.86-2.80(m,2H),1.95-1.76(m,4H),1.44(s,9 H),1.33-1.23(m,1H).

1-[4-[4-[2-[2-(2-aminoethoxy)ethoxy]ethoxymethyl]-1-piperidinyl]phenyl]hexahydropyrimidine Pyridine-2,4-dione (Intermediate IM)

Step 1 - N-[2-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidine- tert-Butyl]-1-yl]phenyl]-4-piperidinyl]methoxy]ethoxy]ethoxy]ethyl]carbamate

A mixture of tert-butyl N-[2-[2-[2-(4-piperidinylmethoxy)ethoxy]ethoxy]ethyl]carbamate (150 mg, 432 μmol, Intermediate IL), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (134 mg, 346 μmol, Intermediate DS), Cs ₂ CO ₃ (564 mg, 1.73 mmol) and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (37.2 mg, 43.2 μmol) in dioxane (2 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 °C under N ₂ atmosphere for 16 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 29%-59%, 15min) to give the title compound (70.0 mg, 24% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 655.2 (M+1) ⁺ .

Step 2-1-[4-[4-[2-[2-(2-aminoethoxy)ethoxy]ethoxymethyl]-1-piperidinyl]phenyl]hexa Hydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]methoxy]ethoxy]ethoxy]ethyl]carbamate (70.0 mg, 106 μmol) in TFA (1.2 mL) was added TfOH (0.396 mg, 2.64 μmol). The mixture was stirred at 70 °C for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (45.0 mg, 96% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 435.1 (M+1) ⁺ .

tert-Butyl N-[3-[(2-chloroacetyl)amino]propyl]carbamate (Intermediate IN)

To a solution of tert-butyl N-(3-aminopropyl)carbamate (1.00 g, 5.74 mmol, CAS#75178-96-0) in THF (10 mL) was added 2-chloroacetyl chloride (1.30 g, 11.4 mmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was diluted with _H2O (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (1.00 g, 70% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43-7.29(m,1H)4.16-4.08(m,6H)3.38(d,J=6.4Hz,2H)3.19(s,2H)1.80-1.63(m,2H)1.45(s,9H).

N-(3-aminopropyl)-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide (Intermediate IO)

Step 1 - N-[3-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]propyl]amino tert-Butyl formate

To a solution of tert-butyl N-[3-[(2-chloroacetyl)amino]propyl]carbamate (5×100 mg, 5×398 μmol, Intermediate IN) in DMF (5×2 mL) was added NaOH (5×63.8 mg, 5×1.60 mmol) and 4-(2,6-dibenzyloxy-3-pyridinyl)phenol (5×45.8 mg, 5×119 μmol, Intermediate IE). The mixture was stirred at 25°C for 16 hr. Upon completion, the reaction mixture was diluted with H ₂ O (10 mL) and extracted with EA (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (170 mg, 14% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.58 (d, J = 8.4Hz, 1H) 7.52 (d, J = 8.8Hz, 2H) 7.46-7.42 (m, 2H) 7.41-7.28 (m, 10H) 6.97 (d, J = 8.8Hz, 2H) 6.48 (d, J = 8Hz, 1H) 5.44-5. 36(m,4H)4.54(s,2H)3.42(d,J＝6.4Hz,2H)3.16(d,J＝6.4Hz,2H)1.69-1.66(m,2H)1.46-1.43(m,9H). LC-MS(ESI ⁺ )m/z 598.1(M+H) ⁺ .

Step 2-N-[3-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]propyl]aminomethoxy Tert-butyl ester

To a solution of tert- _butyl N-[3-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]propyl]carbamate (115 mg, 192 μmol) in THF (2 mL) was added Pd/C (227 mg, 193 μmol) under N atmosphere. The suspension was degassed and purged with _H three times. The mixture was stirred at 25 °C under _H for 2 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (80.0 mg, 99% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 319.9 (M+H) ⁺ .

Step 3 - N-(3-aminopropyl)-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide

To a solution of tert-butyl N-[3-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]propyl]carbamate (80.0 mg, 190 μmol) in DCM (1 mL) was added TFA (1.31 g, 11.4 mmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound as a colorless oil (60.0 mg, 99% yield). LC-MS (ESI ⁺ ) m/z 319.9 (M+H) ⁺ .

Tert-butyl N-[7-[(2-chloroacetyl)amino]heptyl]carbamate (Intermediate IP)

To a solution of tert-butyl N-(7-aminoheptyl)carbamate (600 mg, 2.60 mmol, CAS#99733-18-3) in THF (1 mL) was added TEA (264 mg, 2.60 mmol, 363 μL) and 2-chloroacetyl chloride (353 mg, 3.13 mmol, 249 μL, CAS#79-04-9). The mixture was stirred at 25 °C for 12 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (799 mg, 100% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 329.1 (M+H) ⁺ .

N-(7-aminoheptyl)-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide (Intermediate IQ)

Step 1 - N-[7-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]heptyl]amino tert-Butyl formate

To a solution of tert-butyl N-[7-[(2-chloroacetyl)amino]heptyl]carbamate (799 mg, 2.60 mmol, Intermediate IP) in THF (1 mL) was added NaOH (469 mg, 11.7 mmol) and 4-(2,6-dibenzyloxy-3-pyridinyl)phenol (200 mg, Intermediate IE). The mixture was stirred at 25 °C for 12 hr. Upon completion, the mixture was diluted with _H2O (15 mL) and extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (2 x 10 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50 mm*7 μm; mobile phase: [water(FA)-ACN]; B%: 56%-86%, 20 min) to give the title compound (360 mg, 21% yield) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ7.58(d,J＝8.0Hz,1H),7.55-7.50(m,2H),7.46-7.41(m,2H),7.40-7.29(m,7H),6.97-6.93(m,2H),6.61(t,J＝5.6Hz,1H),6.48(d ,J＝8.0Hz,1H),5.47-5.35(m,4H),4.53(s,2H),3.40-3.32(m,2H),3.10(d,J＝6.0Hz,2H),1.61-1.47(m,4H),1.45(s,10H),1.33(s,7H). LC-MS(ESI ⁺ )m/z 654.2(M+H) ⁺ .

Step 2-N-[7-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]heptyl]aminomethoxy Tert-butyl ester

To a solution of _tert-butyl N-[7-[[2-[4-(2,6-dibenzyloxy-3-pyridyl)phenoxy]acetyl]amino]heptyl]carbamate (257 mg, 393 μmol) in THF (2 mL) was added Pd/C (47 mg, 39.2 μmol, 10 wt%) under N. The suspension was degassed in vacuo and purged with _H several times. The mixture was then stirred under _H (15 psi) at 25 °C for 12 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (150 mg, 81% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ8.02(d,J＝1.2Hz,1H),7.18(d,J＝8.8Hz,2H),6.97-6.91(m,2H),6.52(s,1H),4.50(s,2H),3.75(dd,J＝5.2,10.0Hz,1H),3.39-3.3 0(m,2H),3.10(d,J＝6.0Hz,2H),2.80-2.62(m,2H),2.39-2.12(m,3H),1.45(s,9H),1.44(s,3H),1.31(s,6H). LC-MS(ESI ⁺ )m/z 476.0(M+H) ⁺ .

Step 3 - N-(7-aminoheptyl)-2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetamide

To a solution of tert-butyl N-[7-[[2-[4-(2,6-dioxo-3-piperidinyl)phenoxy]acetyl]amino]heptyl]carbamate (90 mg, 189 μmol) in DCM (0.5 mL) was added TFA (770 mg, 6.75 mmol). The mixture was then stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (70 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 375.7 (M+H) ⁺ .

4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(2-piperidin- (4-(2-(2-oxazin-1-ylethyl)benzenesulfonamide (Intermediate IR)

Step 1-4-[2-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3- Methyl-phenyl]sulfonylamino]ethyl]piperazine-1-carboxylic acid tert-butyl ester

To a solution of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (100 mg, 234 μmol, intermediate DG) in ACN (1.00 mL) and DMF (1 mL) were added DIEA (30.2 mg, 234 μmol, 40.7 μL), Molecular sieves (5.00 mg, 234 μmol) and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (53.0 mg, 234 μmol, CAS#192130-34-0). The mixture was then stirred at 25°C for 10 min. After completion, the mixture was concentrated in vacuo. The mixture was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 19%-49%, 9min) to give the title compound (130 mg, 89% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 620.3 (M+H) ⁺ .

Step 2-4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N- (2-Piperazin-1-ylethyl)benzenesulfonamide

To a solution of tert-butyl 4-[2-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethyl]piperazine-1-carboxylate (89.0 mg, 143 μmol) in DCM (1.00 mL), TFA (1.00 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (80.0 mg, 87% yield, TFA) as a brown oily liquid. LC-MS (ESI ⁺ ) m/z 520.1 (M+H) ⁺ .

Benzyl 4-(4-piperidinylmethoxy)piperidine-1-carboxylate (Intermediate IS)

Step 1-4-(4-pyridyloxymethyl)piperidine-1-carboxylic acid tert-butyl ester

A mixture of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (10 g, 46.5 mmol, CAS#123855-51-6), pyridin-4-ol (4.42 g, 46.5 mmol, CAS#626-64-2), _PPh3 (25.0 g, 93.0 mmol), and DIAD (19.0 g, 93.0 mmol, 18.0 mL) in THF (50 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 25 °C under _N2 atmosphere for 16 hr. Upon completion, the mixture was diluted with _H2O (50 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous _Na2SO4 and concentrated in _vacuo to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (4.90 g, 37% yield) obtained as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 6.0 Hz, 2H), 6.82 (d, J = 6.0 Hz, 2H), 4.18 (d, J = 4.0 Hz, 2H), 3.87 (d, J = 6.4 Hz, 2H), 2.80-2.74 (m, 2H), 2.09-1.90 (m, 1H), 1.82 (d, J = 12.8 Hz, 2H), 1.48 (s, 9H), 1.35-1.23 (m, 2H). LC-MS (ESI ⁺ ) m/z 293.3 (M+H) ⁺ .

Step 2 tert-Butyl 4-(4-piperidinyloxymethyl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(4-pyridyloxymethyl)piperidine-1-carboxylate (2.8 g, 9.58 mmol), _PtO2 (2.17 g, 9.58 mmol), and HOAc (10.50 g, 174.85 mmol, 10 mL) in EtOH (28 mL) was degassed and purged with _H2 three times. The mixture was then stirred at 40 °C under _H2 atmosphere for 16 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give the title compound (2.5 g, 73% yield, HOAc salt) as a white oil. ¹ H NMR (400MHz, CDCl ₃ ) δ4.12(d,J=2.0Hz,2H),3.57(s,1H),3.28-3.18(m,3H),3.13-3.05(m,2H),3.03-2.92(m,1H),2.73-2.69(m,2H),2.05(s,9H), 2.00(s,1H),1.89-1.79(m,2H),1.77-1.63(m,4H),1.31-1.24(m,1H),1.20-1.09(m,2H).

Step 3 4-[(1-Benzyloxycarbonyl-4-piperidinyl)oxymethyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(4-piperidinyloxymethyl)piperidine-1-carboxylate (2.60 g, 7.25 mmol, HOAC) in DCM (30 mL) was added TEA (1.47 g, 14.5 mmol, 2.02 mL) and CbzCl (990 mg, 5.80 mmol, 825 μL, CAS #501-53-1). The mixture was stirred at 25 °C for 3 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15μm; mobile phase: [water (FA)-ACN]; B%: 60%-85%, 22 minutes) to give the title compound (760 mg, 24% yield) as a yellow oil. ¹ HNMR (400MHz, CDCl ₃ ) δ7.39-7.34(m,4H),7.34-7.29(m,1H),5.13(s,2H),4.11(d,J=13.2Hz,2H),3.79(s,2H),3.47-3.41(m,1H),3.30-3.22(m,4H), 2.75-2.65(m,2H),1.80(s,2H),1.72(dd,J=3.2,8.8Hz,3H),1.60-1.56(m,2H),1.46(s,9H),1.19-1.08(m,2H). LC-MS(ESI ⁺ )m/z 433.1(M+H) ⁺ .

Step 4 4-(4-Piperidinylmethoxy)piperidine-1-carboxylic acid benzyl ester

To a solution of tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidinyl)oxymethyl]piperidine-1-carboxylate (650 mg, 1.50 mmol) in DCM (3 mL) was added TFA (4.62 g, 40.5 mmol, 3 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (600 mg, 90% yield, TFA salt) as a yellow oil. LC-MS (ESI ⁺ ) m/z 333.1 (M+H) ⁺ .

3-[3-methyl-2-oxo-4-[4-(4-piperidinyloxymethyl)-1-piperidinyl]benzimidazol-1-yl]piperidin- 2,6-Dione (IT intermediate)

Step 1-4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]methoxy]piperidin-1- Benzyl formate

A mixture of benzyl 4-(4-piperidinylmethoxy)piperidine-1-carboxylate (250 mg, 752 μmol, Intermediate IS), 4-bromo-3-methyl-1H-benzimidazol-2-one (239 mg, 1.05 _mmol , synthesized via steps 1-3 of Intermediate H), _Cs2CO3 (1.47 g, 4.51 mmol), and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (64.7 mg, 75.2 μmol) in dioxane (3 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100 °C under _N2 atmosphere for 12 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50 mm*7 μm; mobile phase: [water(FA)-ACN]; B%: 70%-80%, 23 min) to give the title compound (170 mg, 24% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ9.29 (s, 1H), 7.41-7.29 (m, 5H), 7.02-6.96 (m, 1H), 6.87 (dd, J = 8.0, 12.0Hz, 2H), 5.14 (s, 2H), 3.78 (s, 2H), 3.75 (s, 3H), 3.53-3. 45(m,1H),3.38(d,J＝4.8Hz,2H),3.31-3.24(m,2H),3.20(d,J＝10.0Hz,2H) ,2.79-2.67(m,2H),1.88(d,J＝12.0Hz,5H),1.74-1.59(m,2H),1.51-1.39( m,2H). LC-MS(ESI ⁺ )m/z 479.4(M+H) ⁺ .

Step 2-4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2- [Oxo-benzimidazol-4-yl]-4-piperidinyl]methoxy]piperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]methoxy]piperidine-1-carboxylate (70 mg, 146 μmol) in THF (1 mL) was added t-BuOK (29.5 mg, 263 μmol) and [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (72.5 mg, 190 μmol, Intermediate G). The mixture was stirred at -10 °C for 12 hr. Upon completion, the mixture was quenched with _NH4Cl (1 mL), diluted with _H2O (8 mL), and extracted with EA (2 x 5 mL). The combined organic layers were washed with brine (2 x ₃ mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give the title compound (100 mg, 97% yield) as a green solid. LC-MS(ESI ⁺ )m/z 710.4(M+H) ⁺ .

Step 3-3-[3-methyl-2-oxo-4-[4-(4-piperidinyloxymethyl)-1-piperidinyl]benzimidazole-1- 1-[4-[[(4-[[[[piperidin-2,6-dione] ...

To a solution of 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]methoxy]piperidine-1-carboxylic acid benzyl ester (100 mg, 141 μmol) in TFA (1 mL) was added TfOH (21.1 mg, 141 μmol, 12.5 μL). The mixture was stirred at 70 ° C for 2 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 10 minutes) to give the title compound (20 mg, 32% yield) as a white solid. LC-MS(ESI ⁺ )m/z 456.2(M+H) ⁺ .

tert-Butyl N-[2-(4-piperidinylmethoxy)ethyl]carbamate (Intermediate IU)

Step 1-4-[2-(tert-Butyloxycarbonylamino)ethoxymethyl]piperidine-1-carboxylic acid benzyl ester

A mixture of benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.00 g, 8.02 mmol, CAS#122860-33-7), NaH (641 mg, 16.0 mmol) in DMF (10 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 25 °C under _N2 atmosphere for 0.5 h, and then tert-butyl 2,2-dioxooxathiazolidin-3-carboxylate (3.94 g, 17.6 mmol, CAS#459817-82-4) was added to the mixture. The mixture was stirred at 25 °C under _N2 for 2.5 h. Upon completion, the reaction mixture was quenched with _H2O (10 mL) at 25 °C and then extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 3/1) to give the title compound (1.20 g, 38.1% yield) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.40-7.26 (m, 5H) 6.74 (d, J = 5.2Hz, 1H) 5.06 (s, 2H) 4.00 (d, J = 13.2Hz, 2H) 3.37-3.30 (m, 3H) 3.22 (d, J = 6.4Hz, 2H) 3.06 (d, J = 6 .0Hz,2H)2.81-2.75(m,1H)1.69(s,1H)1.64(d,J＝12.8Hz,2H)1.37(s,9H)1.09-0.99(m,2H).

Step 2-tert-Butyl N-[2-(4-piperidinylmethoxy)ethyl]carbamate

To a solution of 4-[2-(tert-butoxycarbonylamino)ethoxymethyl]piperidine-1-carboxylic acid benzyl ester (1.20 g, 3.06 mmol) in MeOH (2 mL) was added Pd/C (361 mg, 305 μmol) under _N atmosphere. The suspension was degassed and purged with _H three times. The mixture was stirred at 25 °C under _H for 12 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (780 mg, 99% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ )4.86(s,1H)3.46(d,J＝4.8Hz,3H)3.34-3.22(m,4H)3.09(d,J＝12.4Hz,1H)2.61(d,J＝1.6Hz,1H)1.99-1.77(m,1H)1.74-1.69(m,4 H)1.45(s,9H)1.30-1.11(m,2H).

1-[4-[4-(2-aminoethoxymethyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate IV)

Step 1 - N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]benzene tert-butyl]-4-piperidinyl]methoxy]ethyl]carbamate and N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]- 2,4-Dioxo-pyrimidin-1-yl]phenyl]-4-piperidinyl]methoxy]ethyl]carbamic acid tert-butyl ester

1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (607 mg, 1.56 mmol, intermediate DS), tert-butyl N-[2-(4-piperidinylmethoxy)ethyl]carbamate (310 mg, 1.20 mmol, intermediate IU), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (116 mg, 119 μmol), Cs ₂ CO ₃ (781 mg, 2.40 mmol) and A mixture of molecular sieves (2.00 mg) in dioxane (5 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 ° C under N ₂ atmosphere for 16 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18150*25mm*10μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 40%-70%, 8min) to give a crude product (260 mg, 38% yield) of a mixture of the title compounds as a white solid. LC-MS (ESI ⁺ ) m/z (565.4 and 567.4) (M+H) ⁺ .

Step 2-N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]benzene tert-Butyl]-4-piperidinyl]methoxy]ethyl]carbamate

To a solution of tert _-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-pyrimidin-1-yl]phenyl]-4-piperidinyl]methoxy]ethyl]carbamate (260 mg, 460 μmol) in THF (2 mL) was added Pd/C (542 mg, 460 μmol) under N. The suspension was degassed in vacuo and purged with _H three times. The mixture was stirred at 25 °C under _H for 16 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Welch Ultimate C18 150*25mm*5μm; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 10 min) to give the title compound (200 mg, 74% yield) as a colorless oil. LC-MS(ESI ⁺ )m/z 567.3(M+H) ⁺ .

Step 3-1-[4-[4-(2-aminoethoxymethyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]methoxy]ethyl]carbamate (200 mg, 352 μmol) in TFA (2 mL) was added TfOH (680 mg, 4.53 mmol). The mixture was stirred at 70 °C for 1 hour. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (122 mg, quantum yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 346.9 (M+H) ⁺ .

tert-Butyl N-[2-[2-(4-piperidinylmethoxy)ethoxy]ethyl]carbamate (Intermediate IW)

Step 1-4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylic acid benzyl ester

To a solution of ethyl 2-diazoacetate (1.37 g, 12.0 mmol) and benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (1 g, 4.01 mmol, CAS# 122860-33-7) in DCM (10 mL) was added Rh ₂ (OAc) ₄ (178 mg, 401 μmol). The mixture was stirred at 25 °C for 16 hr. Upon completion, the mixture was diluted with H ₂ O (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=100/1 to 8/1) to give the crude product. The crude product was purified by reverse phase (0.1% FA condition) to give the title compound (1.00 g, 64% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.40-7.28(m,5H),5.06(s,2H),4.13-4.07(m,2H),3.99(d,J＝13.2Hz,2H),3.31(d,J＝6.4Hz,2H),2.79(s,2H),1.80-1.70(m ,1H),1.66(d,J＝13.6Hz,2H),1.19(t,J＝7.2Hz,3H),1.10-1.00(m,2H).

Step 2-4-(2-Hydroxyethoxymethyl)piperidine-1-carboxylic acid benzyl ester

A mixture of 4-[(2-ethoxy-2-oxo-ethoxy)methyl]piperidine-1-carboxylic acid benzyl ester (900 mg, 2.68 mmol) in THF (10 mL) and LiAlH ₄ (153 mg, 4.03 mmol) was added to the mixture at 0° C. After 10 minutes, the cooling bath was removed and then stirred at 25° C. for 20 minutes. The mixture was then stirred at 25° C. under N ₂ atmosphere for 2 hr. Upon completion, the mixture was quenched with H ₂ O (1 mL) at 0° C. and then diluted with 15% NaOH (1 mL) solution. The mixture was dried over anhydrous Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo to give the residue as a colorless oil (800 mg, 87% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.41-7.28(m,5H),5.06(s,2H),4.60-4.46(m,1H),4.00(d,J＝13.2Hz,2H),3.48(d,J＝4.4Hz,1H),3.40-3.34(m,2H),3.33(s ,1H),3.24(d,J＝6.4Hz,2H),2.87-2.67(m,2H),1.77-1.69(m,1H),1.66(d,J＝12.8Hz,2H),1.10-1.02(m,2H).

Step 3-4-[2-[2-(tert-Butyloxycarbonylamino)ethoxy]ethoxymethyl]piperidine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-(2-hydroxyethoxymethyl)piperidine-1-carboxylate (800 mg, 2.73 mmol) and tert-butyl 2,2-dioxothiazolidine-3-carboxylate (1.03 g, 4.64 mmol, CAS# 459817-82-4) in THF (8 mL) was added NaH (219 mg, 5.45 mmol, 60% dispersion in mineral oil). The mixture was stirred at 25 °C for 3 hr. Upon completion, the mixture was quenched with H ₂ O (1 mL) at 0 °C and then diluted with H ₂ O (10 mL) and extracted with EA (3×15 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50 mm*15 μm; mobile phase: [water(FA)-ACN]; B%: 55%-75%, 28 min) to give the title compound (300 mg, 26% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.38-7.35(m,4H),7.32(dd,J＝4.0,4.8Hz,1H),7.27(s,1H),5.13(s,2H),4.20(d,J＝7.2Hz,2H),3.61-3.53(m,6H),3.32(d,J＝6 .0Hz,4H),2.83-2.74(m,2H),1.80(dd,J＝6.8,3.6Hz,1H),1.75(d,J＝13.2Hz,2H),1.45(s,9H),1.21-1.10(m,2H). LC-MS(ESI ⁺ )m/z437.4(M+H) ⁺ .

Step 4-tert-Butyl N-[2-[2-(4-piperidinylmethoxy)ethoxy]ethyl]carbamate

To a solution of _benzyl 4-[2-[2-(tert-butoxycarbonylamino)ethoxy]ethoxymethyl]piperidine-1-carboxylate (300 mg, 687 μmol) in MeOH (3 mL) was added Pd/C (407 mg, 344 μmol, 10 wt%) under N. The suspension was degassed in vacuo and purged with _H several times. The mixture was stirred under _H (15 psi) at 25 °C for 12 hr. Upon completion, the mixture was filtered and concentrated under reduced pressure to give the title compound (200 mg, 96% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ5.07-4.89(m,1H),3.64-3.59(m,2H),3.58-3.54(m,4H),3.36-3.30(m,4H),3.09(dd,J=12.4,2.8Hz,1H),2.76-2.58(m,1H),1. 99-1.84(m,1H),1.76-1.71(m,2H),1.61(d,J=2.0Hz,2H),1.45(s,9H),1.34-1.22(m,1H),1.22-1.08(m,2H).

1-[4-[4-[2-(2-aminoethoxy)ethoxymethyl]-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate IX)

Step 1-N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidine-1- tert-butyl]-[4-[[1-[4-[3-[(4-methyl]- [(1-(2-(4-piperidinyl)-2-yl)-1-phenyl]-2,4-dioxo-pyrimidin-1-yl]-phenyl]-4-piperidinyl]-methoxy]-ethoxy]-ethyl]-aminomethyl Tert-butyl ester

A mixture of tert-butyl N-[2-[2-(4-piperidinylmethoxy)ethoxy]ethyl]carbamate (150 mg, 496 μmol, Intermediate IW), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (232 mg, 595 μmol, Intermediate DS), 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (42.7 mg, 49.6 μmol), and _Cs2CO3 (323 mg, 992 μmol) in _dioxane (1 mL) was degassed and purged with _N2 three times. The mixture was then heated at 100°C under N2. ₂ atmosphere for 12 hr. After completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 250*50mm*10μm; mobile phase: [water ( _NH4HCO3 )-ACN]; B%: 41%-71%, ₈ minutes) to give a crude product (140 mg, 47% yield) as a mixture of the title compounds as a yellow solid. LC-MS (ESI ⁺ ) m/z (609.4 and 611.3) (M+H) ⁺ .

Step 2-N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidine-1- tert-butyl]phenyl]-4-piperidinyl]methoxy]ethoxy]ethyl]carbamate

To a solution of tert _-butyl N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-pyrimidin-1-yl]phenyl]-4-piperidinyl]methoxy]ethoxy]ethyl]carbamate (140 mg, 230 μmol) in THF (1 mL) was added Pd/C (272 mg, 10 wt%) under N. The suspension was degassed in vacuo and purged with _H for several times. The mixture was stirred at 25 °C under _H (15 psi) for 12 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5μm; mobile phase: [water (TFA)-ACN]; B%: 22%-52%, 10 min) to give the title compound (80.0 mg, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 611.4 (M+H) ⁺

Step 3-1-[4-[4-[2-(2-aminoethoxy)ethoxymethyl]-1-piperidinyl]phenyl]hexahydropyrimidine-2-yl, 4-Dione

To a solution of tert-butyl N-[2-[2-[[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]methoxy]ethoxy]ethyl]carbamate (80 mg, 131 μmol) in TFA (1 mL) was added TfOH (20 mg, 131 μmol, 12.0 μL). The mixture was stirred at 70 °C for 2 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (51 mg, 99% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 391.1 (M+H) ⁺ .

4-[[6-(Cyclohexyloxy)-9H-purin-2-yl]amino]-N,3-dimethyl-benzenesulfonamide (Intermediate IY)

Step 1-2-Chloro-6-(cyclohexyloxy)-9H-purine

To a solution of cyclohexanol (1.06 g, 10.5 mmol) in DMF (30 mL) was added NaH (846 mg, 21.1 mmol, 60% dispersion in mineral oil) at 0 ° C. The reactant was stirred at 0 ° C for 0.5 hr. Subsequently, 2,6-dichloro-9H-purine (2.00 g, 10.58 mmol, CAS#5451-40-1) was added and the mixture was stirred at 25 ° C for 16 hr. After completion, the mixture was quenched with water (2 mL) at 0 ° C. The mixture was diluted with EA (100 mL) and washed with water (70 mL). Subsequently, the aqueous phase was filtered. The filter cake was dried in vacuo to give the title compound (1.56 g, 58% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 252.8 (M+H) ⁺ .

Step 2-2-Chloro-6-(cyclohexyloxy)-9-tetrahydropyran-2-yl-purine

A mixture of 2-chloro-6-(cyclohexyloxy)-9H-purine (1.56 g, 6.17 mmol), DHP (1.04 g, 12.3 mmol) and TsOH (106 mg, 617 μmol) in THF (22 mL) was stirred at 70 °C for 16 hr. After completion, the reactant was diluted with EA (100 mL). The organic layer was washed with water (100 mL x 3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=10/1 to 3/1) to give the title compound (1.6 g, 76% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.61 (s, 1H), 5.74-5.60 (m, 1H), 5.37-5.24 (m, 1H), 4.01 (d, J = 11.2Hz, 1H), 3.83-3.63 (m, 1H), 2.30-2.18 (m, 1H), 2.08-1.9 1(m,4H),1.81-1.69(m,3H),1.64-1.52(m,5H),1.49-1.37(m,2H),1.36-1.25(m,1H).

Step 3 - N-(4-Benzylthio-2-methyl-phenyl)-6-(cyclohexyloxy)-9-tetrahydropyran-2-yl-purine- 2-Amine

A solution of 2-chloro-6-(cyclohexyloxy)-9-tetrahydropyran-2-yl-purine (1.60 g, 4.75 mmol), 4-benzylsulfanyl-2-methyl-aniline (980 mg, 4.28 mmol, intermediate DE), Pd(OAc) ₂ (106 mg, 475 μmol), BINAP (295 mg, 475 μmol) and Cs ₂ CO ₃ (4.64 g, 14.2 mmol) in toluene (25 mL) was stirred at 100 °C under N ₂ for 4 hr. After completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (100 mL×2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=3/1 to 1/1) to give the title compound (1.6 g, 63% yield) as a red solid. LC-MS(ESI ⁺ )m/z 530.1(M+H) ⁺ .

Step 4-4-[[6-(Cyclohexyloxy)-9H-purin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-6-(cyclohexyloxy)-9-tetrahydropyran-2-yl-purin-2-amine (100 mg, 188 μmol), H ₂ O (34.0 μg, 1.89 μmol) in HOAc (0.3 mL) and ACN (0.9 mL) was added NCS (75.6 mg, 566 μmol). The reaction was stirred at 25 °C in the dark for 1 hr. Upon completion, the reaction was concentrated in vacuo to give the title compound (79.0 mg, 187 μmol, 99% yield) as a green oil. LC-MS (ESI ⁺ ) m/z 422.2 (M+H) ⁺ .

Step 5-4-[[6-(Cyclohexyloxy)-9H-purin-2-yl]amino]-N,3-dimethyl-benzenesulfonamide

To a solution of methylamine hydrochloride (18.9 mg, 280 μmol) and TEA (94.7 mg, 936 μmol) in DCM (2 mL) was added 4-[[6-(cyclohexyloxy)-9H-purin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (79.0 mg, 187 μmol) at 0°C. The reaction was then stirred at 25°C for 1 hr. Upon completion, the reaction was concentrated in vacuo. The residue was purified by prep-HPLC (column: Waters xbridge 150*25mm 10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 26%-56%, 8 min) to give the title compound (14.0 mg, 18% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.92-12.66 (m, 1H), 8.54 (s, 1H), 8.15-7.92 (m, 2H), 7.64-7.50 (m, 2H), 7.27 (q, J = 5.2Hz, 1H), 5.33-5.17 (m, 1H), 2.41 (d, J=5.2Hz, 3H), 2.36 (s, 3H), 2.11-2.00 (m, 2H), 1.81-1.75 (m, 2H), 1.62-1.49 (m, 3H), 1.46-1.20 (m, 3H); LC-MS (ESI ⁺ ) m/z 417.0 (M+H) ⁺ .

3-Methyl-4-[[4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]aminobenzenesulfonyl chloride (Medium Intermediate (IZ)

Step 1 - N-(4-Benzylthio-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine

To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1 g, 4.61 mmol, CAS#3932-97-6) in a mixed solvent of t-BuOH (30 mL) and DCE (30 mL) was added ZnCl ₂ (1 M, 5.53 mL) at 0° C. After 1 hour, a solution of 4-benzylsulfanyl-2-methyl-aniline (1.06 g, 4.61 mmol, intermediate DE) and TEA (513 mg, 5.07 mmol) in a mixed solvent of t-BuOH (15 mL) and DCE (15 mL) was added dropwise to the above solution. The mixture was stirred at 25° C. for 16 hr. After completion, the mixture was quenched with ice water (100 ml) and extracted with DCM (90 ml×3). The combined organic phase was washed with H ₂ O (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=30/1 to 15/1) to give the title compound (1.7 g, 81% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 8.65 (s, 1H), 7.40-7.34 (m, 2H), 7.33-7.27 (m, 3H), 7.26-7.19 (m, 3H), 4.24 (s, 2H), 2.15 (s, 3H); LC-MS (ESI ⁺ ) m/z 409.8 (M+H) ⁺ .

Step 2 - N-(4-Benzylthio-2-methyl-phenyl)-4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidine Pyridin-2-amine

A mixture of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (0.8 g, 1.95 mmol), (1-methylpyrazol-4-yl)boronic acid (491 mg, 3.90 mmol, CAS#847818-55-7), Pd(PPh ₃ ) ₂ Cl ₂ (137 mg, 195 μmol) and Na ₂ CO ₃ (2M, 2.73 mL) in dioxane (23 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 °C under N ₂ atmosphere for 12 hr. Upon completion, the mixture was quenched with ice water (100 ml) and extracted with DCM (50 ml×3). The combined organic phase was washed with H ₂ O (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EA=20/1 to 1/1) to give the title compound (0.8 g, 83% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (s, 1H), 8.62 (s, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.42-7.35 (m, 3H), 7.33-7.27 (m, 2H), 7.26-7.17 (m, 3H), 4.23 (s, 2H), 3.92 (s, 3H), 2.18 (s, 3H); LC-MS (ESI ⁺ ) m/z 456.3 (M+H) ⁺ .

Step 3-3-Methyl-4-[[4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonate Acid chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(1-methylpyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 219 μmol) in HOAc (0.4 mL) and ACN (1.2 mL) was added NCS (87.9 mg, 658 μmol). The mixture was stirred at 25 °C for 1 hr. After completion, the mixture was concentrated to give the title compound (100 mg, 92% yield, HOAc) as a yellow oil. LC-MS (ESI ⁺ ) m/z 431.9 (M+H) ⁺ .

4-[[4-Cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride (Intermediate JA)

Step 1 - N-(4-Benzylthio-2-methyl-phenyl)-4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-amine

To a 40 mL vial equipped with a stir bar was added a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (500 mg, 1.22 mmol, intermediate EA), bromocyclohexane (258 mg, 1.59 mmol), TTMSS (303 mg, 1.22 mmol), NiCl ₂ .dtbbpy (7.28 mg, 18.3 μmol), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (13.6 mg, 12.2 μmol) and Na ₂ CO ₃ (258 mg, 2.44 mmol) in DME (10 mL). The vial was sealed and placed under nitrogen. The reaction was stirred and irradiated with a 10 W blue LED lamp (3 cm away) while the reaction temperature was maintained at 25° C. for 14 hr with cooling water. Upon completion, the reaction mixture was concentrated in vacuo. The mixture was diluted with _H2O (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with saturated NaCl and _H2O (10 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography ( _SiO2 , PE:EA = 50: ₁ to 30:1) and reverse phase (0.1% FA condition) to give the title compound (215 mg, 38% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.40 (s, 1H), 8.53 (s, 1H), 7.37-7.33 (m, 2H), 7.32-7.26 (m, 2H), 7.26-7.19 (m, 2H), 7.15 (dd, J = 2.0, 8.4Hz, 1H), 4.22 (s, 2H), 3.30(s,1H),2.74-2.71(m,1H),2.16(s,3H),1.78-1.75(m,2H),1.70-1.65(m,3H),1.62-1.48(m,2H),1.37-1.13(m,3H). LC-MS(ESI ⁺ )m/z 458.1(M+H) ⁺ .

Step 2-4-[[4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl-benzenesulfonyl chloride

To a solution of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-cyclohexyl-5-(trifluoromethyl)pyrimidin-2-amine (60 mg, 131 μmol) in HOAc (0.5 mL) and ACN (1.5 mL) was added NCS (52.5 mg, 393 μmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (60 mg, 98% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 434.1 (M+H) ⁺ .

Benzyl 4-[2-(4-piperidinyl)ethyl]piperazine-1-carboxylate (Intermediate JB)

Step 1-4-[2-(1-benzyloxycarbonyl-4-piperidinyl)ethyl]piperazine-1-carboxylic acid tert-butyl ester

To a solution of benzyl piperazine-1-carboxylate (1.02 g, 4.62 mmol, 893 μL, CAS#31166-44-6) in THF (10 mL) was added KOAc (4.32 g, 44.0 mmol) dropwise, and then tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1 g, 4.40 mmol, CAS#142374-19-4) was added at 0°C. After addition, the mixture was stirred at this temperature for 30 minutes, and then NaBH(OAc) ₃ (1.86 g, 8.80 mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 1.5 hours. Upon completion, the mixture was diluted with _H2O (20 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with brine (2 x 10 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 5/1) to give the title compound (2.0 g, 88% yield, HOAc salt) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.31 (m, 5H), 5.13 (s, 2H), 4.08 (d, J=12.0 Hz, 2H), 3.59 (t, J=4.8 Hz, 4H), 2.67 (t, J=12.0 Hz, 2H), 2.58-2.48 (m, 6H), 1.63 (d, J=12.4 Hz, 2H), 1.47 (s, 3H), 1.45 (s, 9H), 1.17-1.05 (m, 2H). LC-MS (ESI ⁺ ) m/z 432.5 (M+H) ⁺ .

Step 2-4-[2-(4-piperidinyl)ethyl]piperazine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-[2-(1-tert-butoxycarbonyl-4-piperidinyl)ethyl]piperazine-1-carboxylate (2 g, 4.07 mmol, HOAc) in DCM (10 mL) was added TFA (13.5 g, 119 mmol, 8.80 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (1.8 g, 99% yield, TFA salt) as a white solid. LC-MS (ESI ⁺ ) m/z 332.4 (M+H) ⁺ .

3-[3-methyl-2-oxo-4-[4-(2-piperazin-1-ylethyl)-1-piperidinyl]benzimidazol-1-yl]piperidin- 2,6-Dione (Intermediate JC)

Step 1-4-[2-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]ethyl]piperazine-1- Benzyl formate

A mixture of benzyl 4-[2-(4-piperidinyl)ethyl]piperazine-1-carboxylate (100 mg, 225 μmol, TFA, Intermediate JB), 4-bromo-3-methyl-1H-benzimidazol-2-one (51.0 mg, 225 μmol, synthesized via steps 1-3 of Intermediate H), _Cs2CO3 (439 mg, 1.35 mmol, 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1- _ium -2-chloride; 3-chloropyridine; palladium dichloride (9.66 mg, 11.2 μmol, CAS#1435347-24-2) in dioxane (4 mL) was degassed and purged with _N2 three times. The mixture was then heated at 110 °C under N2. ₂ atmosphere for 12 hr. After completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15μm; mobile phase: [water (FA)-ACN]; B%: 20%-60%, 25 minutes) to give the title compound (50 mg, 43% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.68(s,1H),8.04(s,1H),7.32-7.12(m,5H),6.81-6.74(m,1H),6.66(d,J＝7.6Hz,1H),6.60(dd,J＝0.8,7.6Hz,1H),4.96(s,2H),3.43(s,3H),3.3 1(s,4H),2.94(d,J＝11.2Hz,2H),2.41-2.36(m,2H),2.36-2.27(m,6H),1.62(d,J＝10.0Hz,2H),1.36-1.23(m,4H). LC-MS(ESI ⁺ )m/z 478.2(M+H) ⁺ .

Step 2-4-[2-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl- 2-Oxo-benzimidazol-4-yl]-4-piperidinyl]ethyl]piperazine-1-carboxylic acid benzyl ester

To a solution of benzyl 4-[2-[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]ethyl]piperazine-1-carboxylate (300 mg, 628 μmol) in THF (5 mL) was added t-BuOK (127 mg, 1.13 mmol). After addition, the mixture was stirred at this temperature for 30 minutes, and then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (431 mg, 1.13 mmol, Intermediate G) was added dropwise at -10 °C. The mixture was then stirred at -10 °C for 12 hr. Upon completion, the mixture was quenched with NH ₄ Cl (1 mL), diluted with H ₂ O (8 mL), and extracted with EA (2×5 mL). The organic layer was then washed with brine (2×3 mL), dried over anhydrous Na ₂ SO ₄ , and concentrated in vacuo to give a residue. The crude product was purified by reverse phase HPLC (0.1% FA condition) to give the title compound (350 mg, 77% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.42-7.28 (m, 5H), 7.21 (d, J=8.8 Hz, 2H), 6.95-6.89 (m, 2H), 6.89-6.84 (m, 2H), 6.76 (s, 1H), 5.50 (dd, J=5.2, 12.8 Hz, 1H), 5.08 (s, 2H), 4.88-4.73 (m, 2H), 3.73 (s, 3H), 3. .62(s,3H),3.40(s,4H),3.08(d,J＝11.6Hz,2H),2.86-2.75(m,2H),2.74-2.62(m,4H),2.35(d,J＝4.0Hz,6H),2.08-1.98(m,1H),1.77(d,J＝10.4Hz, 2H),1.50-1.37(m,4H). LC-MS(ESI ⁺ )m/z 709.4(M+H) ⁺ .

Step 3-3-[3-methyl-2-oxo-4-[4-(2-piperazin-1-ylethyl)-1-piperidinyl]benzimidazol-1-yl] Piperidine-2,6-dione

To a solution of 4-[2-[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]ethyl]piperazine-1-carboxylic acid benzyl ester (350 mg, 494 μmol) in TFA (2 mL) was added TfOH (578 mg, 3.85 mmol, 0.34 mL). The mixture was stirred at 70 ° C for 2 hr. After completion, the mixture was concentrated in vacuo to give the title compound (224 mg, 99% yield) as a yellow solid. LC-MS (ESI ⁺ ) m / z 455.0.0 (M + H) ⁺ .

N-[2-(2-aminoethoxy)ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidine- 2-amino]-3-methyl-benzenesulfonamide (Intermediate JD)

Step 1-N-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino tert-butyl]-3-methyl-phenyl]sulfonylamino]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-(2-aminoethoxy)ethyl]carbamate (112 mg, 551 μmol, CAS# 127828-22-2) in DCM (3 mL) was added TEA (1.65 mmol, 230 μL) and 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (250 mg, 551 μmol, Intermediate CW), and the mixture was then stirred at 25° C. for 1 hour. After completion, the mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenexluna C18 (column: Phenomenex C18 150*25mm*10μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 42%-72%, 8min) to give the title compound (150 mg, 43% yield) as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.75(s,1H),8.17(s,1H),7.74-7.68(m,2H),7.66-7.59(m,2H),6.85-6.75(m,1H),5.80-5.67(m,1H),3.35(t,J＝5.6Hz,2H),3.28-3.24(m,3H), 3.07-3.01(m,2H),2.95-2.89(m,2H),2.32(s,3H),2.18-2.04(m,2H),1.76-1.63(m,4H),1.50-1.42(m,2H),1.36(s,9H). LC-MS(ESI ⁺ )m/z 620.8(M+H) ⁺ .

Step 2-N-[2-(2-aminoethoxy)ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d] Pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide

To a solution of tert-butyl N-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]ethyl]carbamate (140 mg, 225 μmol) was added HCl/dioxane (4 mL) and the mixture was then stirred at 25° C. for 1 hour. Upon completion, the mixture was concentrated in vacuo to give the title compound as a white solid (123 mg, 97% yield, HCl). LC-MS (ESI ⁺ ) m/z 520.8 (M+H) ⁺ .

2-[3-(2,4-Dioxohexahydropyrimidin-1-yl)-4-methyl-phenoxy]acetic acid (Intermediate JE)

Step 1-2-(4-methyl-3-nitro-phenoxy)acetic acid methyl ester

To a solution of 4-methyl-3-nitro-phenol (5 g, 30 mmol, CAS# 2042-14-0) in acetone (100 mL) was added methyl 2-bromoacetate (7.49 g, 50 mmol, 4.62 mL) and Cs ₂ CO ₃ (21.28 g, 65.30 mmol) and then the mixture was heated to 60° C. for 16 hr. Upon completion, the reaction was cooled to 20° C. and then poured into water (700 mL) where a solid precipitated. The mixture was filtered and the filter cake was washed with water (100 ml) and then dried in vacuo to give the title compound as a grey solid (5 g, 6% yield).

Step 2-2-(3-amino-4-methyl-phenoxy)acetic acid methyl ester

To a solution of methyl 2-(4-methyl-3-nitro-phenoxy)acetate (5 g, 20 mmol) in MeOH (100 mL) was added Pd/C (0.5 g, 20 mmol, 5 wt%), then the resulting suspension was degassed and then purged with _H gas (15 psi). The reaction was stirred at 20 °C for 2 hr. Upon completion, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (4 g, 20.49 mmol, 92% yield) as a colorless oil.

Step 3-3-[5-(2-methoxy-2-oxo-ethoxy)-2-methyl-phenylamino]propionic acid

To a solution of methyl 2-(3-amino-4-methyl-phenoxy)acetate (4 g, 20 mmol) in _H2O (2 mL) was added acrylic acid (4.43 g, 61.5 mmol, 4.22 mL) and the mixture was stirred at 80 °C for 3 hr. Upon completion, the reaction was concentrated in vacuo to give the title compound as a yellow gum (14 g).

Step 4-2-[3-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-phenoxy]acetic acid

To a solution of 3-[5-(2-methoxy-2-oxo-ethoxy)-2-methyl-phenylamino]propionic acid (13.33 g, 29.93 mmol) in AcOH (30 mL) was added urea (5.39 g, 89.79 mmol, 4.81 mL), and the mixture was heated to 130 ° C for 16 hr. After completion, the reactant was cooled to 20 ° C, HCl (60 ml, 2N) was subsequently added and the mixture was stirred for 10 min. The resulting mixture was poured into water (70 ml), where solids precipitated. The suspension was filtered and the filter cake was washed with water (20 ml). The filter cake was wet-milled with MeOH (10 ml) and then filtered. The filter cake was dried in vacuo to give the title compound (1.30 g, 16% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.97 (br s, 1H), 10.33 (s, 1H), 7.16 (d, J = 8.4Hz, 1H), 6.89 (t, J = 6.8Hz, 1H), 6.81-6.78 (m, 1H), 4.64 (s, 2H), 3.79-3.73 (m, 1H),3.51-3.46(m,1H),2.81-2.60(m,2H),2.01(s,3H). LC-MS(ESI+)m/z 279.2(M+H) ⁺ .

2-(4-Chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetic acid (Intermediate JF)

Step 1-2-(4-chloro-3-nitro-phenoxy)acetic acid methyl ester

To a solution of 4-chloro-3-nitro-phenol (10 g, 60 mmol, _CAS #610-78-6) in DMF (100 mL) was added 2-bromoacetate (10.58 g, 69.14 mmol, 6.53 mL, CAS#96-32-2) and _K2CO3 (15.93 g, 115.2 mmol). The mixture was stirred at 25 °C for 2 hr. Upon completion, the reaction mixture was partitioned between water (50 mL) and EtOAc (35 mL). The organic phase was separated, washed with water (20 mL x ₃ ), dried over _Na2SO4 , filtered and concentrated under reduced pressure to give the title compound (10 g, 71% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ = 7.47-7.29 (m, 2H), 7.02 (dd, J = 3.0, 8.9Hz, 1H), 4.62 (s, 2H), 3.75 (s, 3H). LC-MS(ESI+)m/z 215.0(M-30) ⁺ .

Step 2-2-(3-amino-4-chloro-phenoxy)acetic acid methyl ester

To a solution of methyl 2-(4-chloro-3-nitro-phenoxy)acetate (10 g, 40 mmol) in MeOH (40 mL) was added iron powder (6.82 g, 122.14 mmol), NH ₄ Cl (10.89 g, 203.6 mmol) and water (130 mL) at 25° C. The mixture was stirred at 60° C. for 4 hr. Upon completion, the reaction mixture was partitioned between water (100 mL) and EtOAc (30 mL). The organic phase was separated, washed with water (20 mL×3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=5:1, R _f =0.6) to give the title compound (8 g, 89% yield) as a yellow solid. ¹ H NMR (400MHz,) δ = 7.14 (s, 1H), 7.12 (s, 1H), 7.17-7.09 (m, 1H), 6.35 (d, J = 2.8Hz, 1H), 6.25 (dd, J = 2.8, 8.7Hz, 1H), 4.58 (s, 2H), 4.16-4.02 (m, 2H), 3. 84-3.78(m,1H),3.80(s,2H),2.05(s,1H),1.26(t,J＝7.2Hz,1H). LC-MS(ESI+)m/z 216.0(M+H) ⁺ .

Step 3-2-[4-chloro-3-(2,4-dioxohexahydropyrimidin-1-yl)phenoxy]acetic acid

A mixture of methyl 2-(3-amino-4-chloro-phenoxy)acetate (4 g, 19 mmol) and acrylic acid (5.35 g, 74.2 mmol, 5.09 mL) was stirred at 120 °C for 4 hr. AcOH (40 mL) and urea (5.57 g, 92.8 mmol, 4.97 mL) were then added at 20 °C. The resulting mixture was stirred at 120 °C for 12 hr. Upon completion, the reaction mixture was poured into a mixture of water (100 mL) and HCl (12 M, 1.55 mL), and the mixture was stirred at 20 °C for 0.5 hr. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by combi-flash (0.1% TFA) to give the title compound (358.67 mg, 6% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 13.34-12.83 (m, 1H), 10.46 (s, 1H), 7.50-7.41 (m, 1H), 7.14 (d, J = 2.8Hz, 1H), 6.99 -6.89 (m, 1H), 4.71 (s, 2H), 3.81-3.50 (m, 2H),2.82-2.63(m,2H)LC-MS(ESI+)m/z 299.0(M+H) ⁺ .

N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2, 3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide (Intermediate JG)

Step 1-N-[2-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino tert-butyl]-3-methyl-phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]carbamate

To a solution of tert-butyl N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]carbamate (137 mg, 551 μmol, CAS# 153086-78-3) in DCM (4 mL) was added TEA (167 mg, 1.65 mmol) until pH = 7-8. Then 4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (250 mg, 551 μmol, Intermediate CW) was added. Then the mixture was stirred at 25 °C for 0.5 hr. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 150*25 mm*10 μm; mobile phase: [water(NH ₄ HCO ₃ )-ACN]; B%: 42%-72%, 8 min) to give the title compound (90.0 mg, 24% yield) as a white solid. ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.66 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 7.72-7.68 (m, 2H), 7.67-7.60 (m, 2H), 6.74 (t, J = 5.4Hz, 1H), 5.79-5.68 (m, 1H), 3.4 7-3.38(m,7H),3.09-3.02(m,2H),2.92-2.87(m,2H),2.32(s,3H),2.17-2.03(m,2H),1.69(s,4H),1.45(s,3H),1.35(s,9H). LC-MS(ESI ⁺ )m/z 664.8(M+H) ⁺ .

Step 2-N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[(6-chloro-8-cyclopentyl-7-oxo-pyrrolidone)- [2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonamide

To a solution of tert-butyl N-[2-[2-[2-[[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonylamino]ethoxy]ethoxy]ethyl]carbamate (70.0 mg, 105 μmol) in HCl/dioxane (2 mL) and the mixture was stirred at 25° C. for 0.5 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (62.0 mg, 97% yield, HCl) as a white solid. LC-MS (ESI ⁺ ) m/z 565.0 (M+H) ⁺ .

4-Chloro-3-(2,4-dioxohexahydropyrimidin-1-yl)benzoic acid (Intermediate JH)

tert-Butyl N-[3-(4-piperidinyl)propyl]carbamate (Intermediate JI)

Step-1-tert-Butyl N-[3-(4-pyridyl)propyl]carbamate

To a solution of 3-(4-pyridinyl)propan-1-amine (1.00 g, 7.34 mmol, CAS# 30532-36-6) in DCM (10 mL) was added Boc ₂ O (1.92 g, 8.81 mmol) and Et ₃ N (1.49 g, 14.6 mmol). The mixture was stirred at 25 °C for 2 hr. Upon completion, the residue was diluted with H ₂ O (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (2×6 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 1/1) to give the title compound (1.50 g, 85% yield) as a colorless oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.49 (d, J = 6.0 Hz, 2H) 7.12 (d, J = 5.6 Hz, 2H) 4.63 (s, 1H) 3.16 (d, J = 6.4 Hz, 2H) 2.66-2.61 (m, 2H) 1.86-1.78 (m, 2H) 1.44 (s, 9H). LC-MS(ESI ⁺ )m/z 237.1(M+H) ⁺ .

Step 2-tert-Butyl N-[3-(4-piperidinyl)propyl]carbamate

To a solution of tert _-butyl N-[3-(4-pyridinyl)propyl]carbamate (1.50 g, 6.35 mmol) in EtOH (12 mL) was added _PtO (1.44 g, 6.35 mmol) and AcOH (6.30 g, 104 mmol) under N atmosphere. The suspension was degassed and purged with _H three times. The mixture was stirred under _H at 40 °C for 16 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (1.50 g, 98% yield) as a colorless oil. ¹ H NMR (400MHz, CDCl ₃ ) δ3.37 (d, J = 12.8Hz, 2H) 3.09 (d, J = 5.2Hz, 2H) 2.81 (t, J = 12.4Hz, 2H) 1.82 (d, J = 11.6Hz, 2H) 1.69-1.56 (m, 1H) 1.52-1.46 (m, 5H) 1.43 (s,9H)1.31(d,J=5.6Hz,2H)1.28-1.22(m,1H).

1-[4-[4-(3-aminopropyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione (Intermediate JJ)

Step 1 - N-[3-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]benzene tert-Butyl]-4-piperidinyl]propyl]carbamate

A mixture of tert-butyl N-[3-(4-piperidinyl)propyl]carbamate (233 mg, 963 μmol, Intermediate JI), 1-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (150 mg, 385 μmol, Intermediate DS), 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (37.4 mg, 38.5 μmol), and Cs ₂ CO ₃ (502 mg, 1.54 mmol) in dioxane (3 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 °C under N ₂ atmosphere for 16 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18 150*25mm*10μm; mobile phase: [ _water ( _NH4HCO3 )-ACN]; B%: 46%-76%, 8min) to give the title compound (130mg, 60% yield) as a white solid. ^1H NMR (400MHz, _CDCl3 ) δ7.43 (d, J=8.8Hz, 2H)7.12 (d, J=8.8Hz, 2H)6.92 (d, J=8.8Hz, 2H)6.83 (d, J=8.4Hz, 2H)4.95 (s, 2H)3.79 (s, 3H)3.72 (t, J=6.8Hz, 2H)3.65 (d, J=12.4Hz, 2H) )3.17-3.08(m,2H)2.85(t,J＝6.8Hz,2H)2.74-2.64(m,2H)1.78(d,J＝11.2Hz,2H)1.51(d,J＝7.6Hz,3H)1.46(s,9H)1.35(d,J＝12.0Hz,2H)1.33-1.26(m ,3H). LC-MS(ESI ⁺ )m/z 551.0(M+H) ⁺ .

Step 2-1-[4-[4-(3-aminopropyl)-1-piperidinyl]phenyl]hexahydropyrimidine-2,4-dione

To a solution of tert-butyl N-[3-[1-[4-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]phenyl]-4-piperidinyl]propyl]carbamate (70.0 mg, 127 μmol) in TFA (1 mL) was added TfOH (340 mg, 2.27 mmol). The mixture was stirred at 70 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (42.0 mg, 100% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 330.9 (M+H) ⁺ .

3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidinyl]-2-oxo-benzimidazol-1-yl]piperidin-2,6- Diketone (Intermediate JK)

Step 1: N-methyl-N-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]methyl]amino tert-Butyl formate

A mixture of 4-bromo-3-methyl-1H-benzimidazol-2-one (0.85 g, 3.74 mmol, synthesized via steps 1-3 of Intermediate H), tert-butyl N-methyl-N-(4-piperidinylmethyl)carbamate (940 mg, 4.12 mmol, CAS# 138022-04-5), RuPhos (174 mg, 374 μmol), Pd ₂ (dba) ₃ (342 mg, 374 μmol) and t-BuOK (1.26 g, 11.2 mmol) in dioxane (20 mL) was stirred at 90 °C under N ₂ for 16 hr. After completion, the reaction was diluted with EA (100 mL). The organic layer was washed with water (70 mL x 3), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , DCM/ethyl acetate = 0% to 35%) to give the title compound (800 mg, 57% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 375.3 (M+H) ⁺ .

Step 2-N-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2- [Oxo-benzoimidazol-4-yl]-4-piperidinyl]methyl]-N-methyl-carbamic acid tert-butyl ester

To a solution of tert-butyl N-methyl-N-[[1-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]methyl]carbamate (460 mg, 1.23 mmol) in THF (10 mL) was added t-BuOK (413 mg, 3.69 mmol) at 0°C. The reactant was stirred at 0°C for 0.5 hr. Subsequently, [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (702 mg, 1.84 mmol, intermediate G) was added to the above mixture at 0°C. The reactant was stirred at 25°C for 1.5 hr. After completion, the reactant was diluted with EA (100 mL). The organic layer was washed with water (100 mL×2) and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , DCM/ethyl acetate = 100/0 to 50/50) to give the title compound (400 mg, 53% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 606.4 (M+H) ⁺ .

Step 3-3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidinyl]-2-oxo-benzimidazol-1-yl]piperidinyl Pyridine-2,6-dione

A mixture of N-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]methyl]-N-methyl-carbamic acid tert-butyl ester (270 mg, 445 μmol) and TfOH (1.38 g, 9.18 mmol) in TFA (1 mL) was stirred at 70° C. for 1 hr. After completion, the reaction was concentrated in vacuo to give the title compound (222 mg, 99% yield, TFA) as a brown oil. LC-MS (ESI ⁺ ) m/z 386.0 (M+H) ⁺ .

Step 4-N-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4- [piperidinyl]methyl]-N-methyl-carbamic acid tert-butyl ester

To a mixture of 3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (222 mg, 444 μmol, TFA) and TEA (134 mg, 1.33 mmol) in DCM (2 mL) was added Boc ₂ O (145 mg, 666 μmol). The reactant was stirred at 25 °C for 1 hr. After completion, the reactant was diluted with EA (100 mL). The organic layer was washed with water (70 mL×2), dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The crude product was triturated with PE:EA=10:1 (10 mL) at 25 °C for 30 min to give the title compound (200 mg, 92% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 486.4 (M+H) ⁺ .

Step 5-3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidinyl]-2-oxo-benzimidazol-1-yl]piperidinyl Pyridine-2,6-dione

A mixture of N-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]methyl]-N-methyl-carbamic acid tert-butyl ester (200 mg, 411 μmol) and TFA (770 mg, 6.75 mmol, 0.5 mL) in DCM (2 mL) was stirred at 25° C. for 1 hr. After completion, the reaction was concentrated in vacuo to give the title compound as a brown oil (205 mg, 99% yield, TFA). LC-MS (ESI ⁺ ) m/z 386.1 (M+H) ⁺ .

3-[3-methyl-4-[4-[[methyl(4-piperidinyl)amino]methyl]-1-piperidinyl]-2-oxo-benzimidazole- 1-yl]piperidine-2,6-dione (Intermediate JL)

Step 1-4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4- [piperidinyl]methyl-methyl-amino]piperidin-1-carboxylic acid tert-butyl ester

To a solution of 3-[3-methyl-4-[4-(methylaminomethyl)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (202 mg, 404 μmol, TFA, intermediate CL), TEA (40.9 mg, 404 μmol) and HOAc (48.5 mg, 808 μmol) in DMF (1 mL) and THF (3 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (241 mg, 1.21 mmol, CAS#79099-07-3). The reaction was stirred at 25 °C for 0.5 hr. NaBH(OAc) ₃ (128 mg, 606 μmol) was then added and the mixture was stirred at 40 °C for 1.5 hr. Upon completion, the mixture was quenched with water (0.05 mL) and diluted with EA (70 mL). The organic layer was washed with water (70 mL) and concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 12%-42%, 10 min) to give the title compound (130 mg, 56% yield) as a brown solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08 (s, 1H), 7.02-6.96 (m, 1H), 6.94-6.86 (m, 2H), 5.42-5.37 (m, 1H), 4.68 (d, J = 3.6Hz, 2H), 4.17-4.02 (m, 2H), 3.63 (s, 3H) ,3.15(d,J＝10.0Hz,2H),2.94(s,4H),2.78(s,3H),2.02-1.90(m,4H),1.72-1.62(m,5H),1.41(s,9H),1.30-1.16(m,5H); LC-MS(ESI ⁺ )m/z 569.3(M+H) ) ⁺ .

Step 2-3-[3-methyl-4-[4-[[methyl(4-piperidinyl)amino]methyl]-1-piperidinyl]-2-oxo-benzo Imidazol-1-yl]piperidine-2,6-dione

A mixture of tert-butyl 4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]methyl-methyl-amino]piperidine-1-carboxylate (50.0 mg, 87.9 μmol) in HCl/dioxane (4M, 2 mL) was stirred at 25° C. for 1 hr. After completion, the residue was concentrated in vacuo to give the title compound as a white solid (44 mg, 99% yield, HCl). LC-MS (ESI ⁺ ) m/z 469.2 (M+H) ⁺ .

3-[4-(2,7-diazaspiro[3.5]non-7-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidin-2,6- Diketone (Intermediate JM)

Step 1-7-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid Tert-butyl ester

To tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (2.00 g, 8.84 mmol, CAS# 236406-55-6), 4-bromo-3-methyl-1H-benzimidazol-2-one (2.21 g, 9.72 mmol, synthesized via steps 1-3 of Intermediate H) in dioxane (20 mL) were added Cs ₂ CO ₃ (5.76 g, 17.6 mmol), Molecular sieves and 1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (380 mg, 441 μmol) and the mixture was purged with N ₂ three times. The mixture was then stirred at 110 ° C under N ₂ atmosphere for 16 hours. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15μm; mobile phase: [water (FA)-ACN]; B%: 55%-65%, 22min) to give the title compound (1.4 g, 41% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.77 (s, 1H), 6.90-6.84 (m, 1H), 6.79-6.75 (m, 1H), 6.70 (d, J = 7.6Hz, 1H), 3.62 (d, J = 2.0Hz, 2H), 3.52 (s, 3H), 2.95 (d, J = 2. 0Hz,2H),2.63-2.56(m,2H),1.83(s,6H),1.37(s,9H).

Step 2-7-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo [4-(2-Benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

To a solution of tert-butyl 7-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (900 mg, 2.42 mmol) in THF (5 mL) was added t-BuOK (488 mg, 4.35 mmol) and stirred at -10°C for 30 min. Then [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (921 mg, 2.42 mmol, Intermediate G) was dissolved in THF (5 mL) and added to the mixture, and then it was stirred at -10°C for 3 hr. Upon completion, the reaction mixture was quenched with _NH4Cl (10 mL) at 25°C, and then diluted with _H2O (50 mL) and extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water(FA)-ACN]; B%: 49%-79%, 22 min) to give the title compound (647 mg, 44% yield) as a grey solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.19 (d, J = 8.8 Hz, 2H), 6.92-6.82 (m, 4H), 6.76 (s, 1H), 5.50-5.45 (m, 1H), 4.86-4.69 (m, 2H), 3.71 (s, 3H), 3.66 (s, 2H), 3.60 ( s,3H),3.58-3.52(m,2H),3.02-2.95(m,2H),2.81-2.80(m,1H),2.75(s,1H),2.69-2.61(m,2H),2.05-1.98(m,1H),1.85(s,4H),1.38(s,9H).

Step 3-3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidin Pyridine-2,6-dione

To a solution of tert-butyl 7-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]nonane-2-carboxylate (200 mg, 331 μmol) in TFA (1.2 mL) was added TfOH (340 mg, 2.27 mmol). The mixture was then stirred at 70 °C for 2 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (160 mg, 97% yield, TFA salt) as a white solid. LC-MS (ESI ⁺ ) m/z 384.1 (M+H) ⁺ .

3-[3-methyl-2-oxo-4-[2-(4-piperidinyl)-2,7-diazaspiro[3.5]non-7-yl]benzimidazole-1- [4-(2-[4-(2-piperidin-2,6-dione)]]piperidin-2,6-dione (Intermediate JN)

Step 1-5-Bromo-N-cyclopentyl-2-methylsulfanyl-pyrimidin-4-amine

To a solution of 3-[4-(2,7-diazaspiro[3.5]nonan-7-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (160 mg, 321 μmol, TFA salt, intermediate JM) in THF (1 mL) and DMF (0.5 mL) was added AcOK (315 mg, 3.22 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (76.9 mg, 385 μmol, CAS#79099-07-3) at -10°C for 1 hr. Then NaBH(OAc) ₃ (136 mg, 643 μmol) and the mixture were added at -10°C. The mixture was then stirred at -10°C for 1 hr. Upon completion, the reaction mixture was quenched with _H2O (1 mL) at 25°C and then filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Welch Xtimate C18 150*25 mm*5 μm; mobile phase: [water(FA)-ACN]; B%: 5%-35%, 10 min) to give the title compound (90 mg, 49% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.08 (s, 1H), 7.00-6.95 (m, 1H), 6.88-6.86 (m, 2H), 5.36-5.32 (m, 1H), 3.90 (d, J = 12.4Hz, 2H), 3.62 (s, 4H), 3.49 (d, J = 2.8Hz, 2H),3.01(s,2H),2.92-2.84(m,2H),2.77(s,1H),2.70-2.63(m,3H),2.3 7-2.31(m,1H),2.03-1.74(m,8H),1.43(s,1H),1.40(s,9H),1.17-1.04(m ,2H).

Step 2-3-[3-methyl-2-oxo-4-[2-(4-piperidinyl)-2,7-diazaspiro[3.5]non-7-yl]benzo Imidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 4-[7-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]-2,7-diazaspiro[3.5]non-2-yl]piperidine-1-carboxylate (50.0 mg, 88.2 μmol) in DCM (2 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (40 mg, 97% yield, TFA salt) as a red solid. LC-MS (ESI ⁺ ) m/z 467.2 (M+1) ⁺ .

6-Chloro-8-isopropyl-2-[2-methyl-4-[(4-piperazin-1-yl-1-piperidinyl)sulfonyl]phenylamino]pyridinol [2,3-d]pyrimidin-7-one (Intermediate JO)

Step 1-4-[1-[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3- Methyl-phenyl]sulfonyl-4-piperidinyl]piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 4-(4-piperidinyl)piperazine-1-carboxylate (69.3 mg, 257 μmol, CAS# 205059-24-1) and TEA (118 mg, 1.17 mmol) in DCM (1 mL) was added a solution of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzenesulfonyl chloride (100 mg, 234 μmol, Intermediate DG) in DCM (1 mL ₎ at 0°C. The reaction mixture was stirred at 25°C for 1 hr. Upon completion, the reaction mixture was diluted with DCM (20 mL) and washed with _H2O (10 mL x 3). The organic layer was dried over _Na2SO4 , filtered and concentrated in vacuo to give the title compound (150 mg, 97% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.69 (s, 1H), 8.75 (s, 1H), 8.17 (s, 1H), 7.80 (d, J = 7.6Hz, 1H), 7.64 (d, J = 1.6Hz, 1H), 7.57 (dd, J = 2.0, 8.4Hz, 1H), 5.61 (d, J = 3. 2Hz,1H),3.68(d,J＝11.6Hz,2H),3.24(s,4H),2.39-2.31(m,7H),2.26-2.17(m,3H),1.77(d,J＝10.4Hz,2H),1.44-1.35(m,17H).

Step 2-6-Chloro-8-isopropyl-2-[2-methyl-4-[(4-piperazin-1-yl-1-piperidinyl)sulfonyl]phenylamino] Pyrido[2,3-d]pyrimidin-7-one

A solution of tert-butyl 4-[1-[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]sulfonyl-4-piperidinyl]piperazine-1-carboxylate (100 mg, 151 μmol) in HCl/dioxane (2 mL) was stirred at 25° C. for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (90 mg, 99% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 560.0 (M+H) ⁺ .

3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2- 6-Diketone (Intermediate JP)

Step 1-9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate Tert-butyl ester

A mixture of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (1.00 g, 3.93 mmol, CAS# 173405-78-2), 4-bromo-3-methyl-1H-benzimidazol-2-one (892 mg, _3.93 mmol, synthesized via steps 1-3 of Intermediate H), _Cs2CO3 (2.56 g, 7.86 mmol), and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-chloride; 3-chloropyridine; palladium dichloride (382 mg, 393 μmol) in dioxane (20 mL) was degassed and purged with _N2 three times. The mixture was then stirred at 100 °C under _N2 atmosphere for 12 hr. After completion, the reaction mixture was diluted with _H2O (20 mL) and extracted with EA (3×20 mL). The combined organic layers were washed with brine (2×10 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 250*50mm*15μm; mobile phase: [water(FA)-ACN]; B%: 60%-70%, 25min) to give the title compound (1.17 g, 36% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ9.86 (s, 1H) 7.02-6.96 (m, 1H) 6.93-6.84 (m, 2H) 3.76 (s, 3H) 3.47-3.39 (m, 4H) 2.96 (s, 4H) 1.74 (s, 2H) 1.65 (d, J = 10.0Hz, 4H) 1. 48(s,9H)1.45-1.35(m,2H). LC-MS(ESI ⁺ )m/z 401.1(M+H) ⁺ .

Step 2-9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo [4-(2-(4-(2-benzoimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

To a solution of tert-butyl 9-(3-methyl-2-oxo-1H-benzimidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.25 mmol) in THF (5 mL) was added t-BuOK (252 mg, 2.25 mmol) and [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (714 mg, 1.87 mmol, Intermediate G). The mixture was stirred at -10 °C for 12 hr. Upon completion, the reaction mixture was quenched with aqueous _NH4Cl solution (2 mL) at 25 °C and diluted with _H2O (5 mL) and extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 65%-95%, 10 min) to give the title compound (350 mg, 44% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.39-7.35(m,2H)6.95-6.87(m,2H)6.85-6.81(m,2H)6.28(d,J＝7.2Hz,1H)5.21(d,J＝5.2Hz,1H)5.02-4.92(m,2H)3.80(s,3H)3. 77(s,3H)3.46-3.40(m,4H)3.04-2.98(m,1H)2.95(s,4H)2.87-2.77(m,1H)2.61(d,J＝4.0Hz,1H)2.15(d,J＝2.4Hz,1H)1.56-1.80(m,8H)1.48(s,9H). LC-MS(ESI ⁺ )m/z 632.4(M+H) ⁺ .

Step 3-3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl] Piperidine-2,6-dione

To a solution of tert-butyl 9-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 316 μmol) in TfOH (0.3 mL) was added TFA (3.08 g, 27.0 mmol). The mixture was stirred at 70 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (130 mg, quantum yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 412.3 (M+H) ⁺ .

3-[3-methyl-2-oxo-4-[3-(4-piperidinyl)-3,9-diazaspiro[5.5]undec-9-yl]benzimidazole- 1-yl]piperidine-2,6-dione (Intermediate JQ)

Step 1-4-[9-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-3,9- tert-Butyl diazaspiro[5.5]undec-3-yl]piperidine-1-carboxylate

To a solution of 3-[4-(3,9-diazaspiro[5.5]undec-3-yl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (30.0 mg, 72.9 μmol, intermediate JP) in THF (0.5 mL) and DMF (0.5 mL) was added tert-butyl 4-oxopiperidine-1-carboxylate (217 mg, 1.09 mmol) and KOAc (35.7 mg, 364 μmol). After 0.5 hr, NaBH(OAc) ₃ (30.9 mg, 145 μmol) was added to the mixture, which was then stirred at 25 °C for 12 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: Phenomenex C18 150*25mm*10μm; mobile phase: [ _water ( _NH4HCO3 )-ACN]; B%: 30%-60%, 8min) to give the title compound (35.0 mg, 79% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 595.7 (M+H) ⁺ .

Step 2-3-[3-methyl-2-oxo-4-[3-(4-piperidinyl)-3,9-diazaspiro[5.5]undec-9-yl]benzene [[(-imidazol-1-yl]piperidin-2,6-dione]]

To a solution of tert-butyl 4-[9-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undec-3-yl]piperidine-1-carboxylate (35.0 mg, 58.8 μmol) in DCM (1 mL) was added TFA (770 mg, 6.75 mmol). The mixture was stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound (29.0 mg, quantum yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 495.4 (M+H) ⁺ . tert -Butyl N-(3- piperazin-1-ylcyclobutyl)carbamate (Intermediate JR)

Step 1-[3-(tert-Butyloxycarbonylamino)cyclobutyl]4-methylbenzenesulfonate

To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (4.0 g, 21.4 mmol, CAS#389890-43-1), pyridine (10.1 g, 128 mmol) and DMAP (2.61 g, 21.4 mmol) in DCM (80 mL) was added TosCl (7.74 g, 40.6 mmol) at 0°C, and then the mixture was stirred at 20°C for 16 hr. After completion, the reaction was washed with 20% citric acid (45 ml x 3 ₎ and brine (50 ml). The organic layer was dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography ( _SiO2 , PE/EA = 10/1 to 1/1) to give the title compound (6.26 g, 85% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.81-7.73(m,2H),7.47(d,J＝8.0Hz,2H),7.13(d,J＝8.0Hz,1H),4.53-4.46(m,1H),3.62-3.48(m,1H),2.42(s,3H),2.02-1. 92(m,2H),1.36(s,2H),1.33(s,9H), LC-MS(ESI+)m/z 242.0(M-100+H) ⁺ .

Step 2-4-[3-(tert-Butyloxycarbonylamino)cyclobutyl]piperazine-1-carboxylic acid benzyl ester

A solution of [3-(tert-butoxycarbonylamino)cyclobutyl]4-methylbenzenesulfonate (3.0 g, 8.79 mmol), benzyl piperazine-1-carboxylate (4.84 g, 21.8 mmol, CAS#31166-44-6), and DMAP (107 mg, 879 μmol) in DMF (40 mL) was degassed and purged with N ₂ three times. The mixture was then stirred at 100 ° C. under N ₂ atmosphere for 16 hr. After completion, the reaction mixture was cooled to rt, diluted with water (200 ml), and extracted with EA (50 ml×4). The organic layers were combined, washed with brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (970 mg, 25% yield, FA) as a yellow oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.16(s,1H),7.43-7.21(m,5H),5.12-5.05(m,2H),4.25-4.13(m,1H),4.07-3.80(m,2H),2.77-2.65(m,1H),2.28-2.15(m, 4H), 2.15-1.85 (m, 6H), 1.36 (s, 9H), LC-MS (ESI+) m/z 390.2 (M+H) ⁺ .

Step 3-tert-Butyl N-(3-piperazin-1-ylcyclobutyl)carbamate

To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)cyclobutyl]piperazine-1-carboxylate (300 mg, 770 μmol, FA) in THF (5 mL) was added Pd/C (100 mg, 10 wt%) under Ar. The suspension was degassed in vacuo and purged with H ₂ three times. It was then stirred at 20° C. under H ₂ (15 psi) atmosphere for 4 hr. Upon completion, the reaction was filtered to give a filtrate, which was then concentrated in vacuo to give the title compound (190 mg, 96% yield) as a yellow oil. ¹ H NMR (400MHz, CDCl ₃ ) δ6.98 (s, 1H), 5.20-4.60 (m, 1H), 4.28-3.93 (m, 1H), 2.89 (t, J = 4.8Hz, 2H), 2.42-2.17 (m, 5H), 2.00-1.95 (m, 2H), 1.44 (s, 9H), 1.32-1.21(m,3H),0.89(s,1H).

3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzene [(1-imidazol-1-yl]piperidine-2,6-dione) (Intermediate JS)

Step 1-N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazole-5- tert-butyl]-4-piperidinyl]methyl]piperazin-1-yl]cyclobutyl]carbamate

To a solution of 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidine-4-carbaldehyde (228 mg, 548 μmol, FA, intermediate DM) in THF (4 mL) was added TEA (55.5 mg, 548 μmol) and the mixture was then stirred at -10 °C for 15 min. Then, tert-butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (140 mg, 548 μmol, intermediate JR) and HOAc (32.9 mg, 548 μmol) were added and the mixture was stirred at -10 °C for 15 min. Finally, NaBH(OAc) ₃ (151 mg, 713 μmol) was added and the mixture was stirred at -10 °C for 1 hr. Upon completion, the mixture was quenched with water (0.3 ml) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]) to give the title compound (80 mg, 22% yield, FA) as an off-white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ8.35 (s, 1H), 6.72-6.62 (m, 3H), 6.44-5.67 (m, 3H), 5.19 (dd, J = 5.2, 12.4Hz, 1H), 4.83 (s, 1H), 4.05 (s, 1H), 3.54 (d, J = 10.8Hz, 2H) ,3.40(s,3H),3.28-3.17(m,1H),2.97-2.45(m,16H),2.29-2.07(m,3H),1.89(d,J＝12.4Hz,2H),1.74(s,1H),1.45(s,9H),LC-MS(ESI+)m/z 610.2(M+ H) ⁺ .

Step 2-3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo [-Benzimidazol-1-yl]piperidine-2,6-dione

A solution of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]cyclobutyl]carbamate (60 mg, 91.5 μmol, FA) in HCl/dioxane (2.0 mL) was stirred at 20°C for 1 hr. Upon completion, the reaction was concentrated in vacuo to afford the title compound (48 mg, 96% yield, HCl) as an off-white solid. LC-MS (ESI+) m/z 510.4 (M+H) ⁺ .

Tert-butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (Intermediate JT)

Step 1-[3-(tert-Butyloxycarbonylamino)cyclobutyl]4-methylbenzenesulfonate

To a solution of tert-butyl N-(3-hydroxycyclobutyl)carbamate (2 g, 10.68 mmol, CAS #98-59-9) in pyridine (15 mL) was added 4-methylbenzenesulfonyl chloride (3.05 g, 16.0 mmol), and the reaction mixture was then stirred at 50 °C for 12 hr. Upon completion, the reaction mixture was quenched with _H2O (30 mL) and extracted with EA (2 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried _over anhydrous _Na2SO4 , filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography ( _SiO2 , PE:EA = 50:1 to PE:EA = 3:1, PE:EA = 3:1, P1:Rf = 0.32) to give the title compound (3.3 g, 90% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.76 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.03-4.76 (m, 1H), 3.88-3.68 (m, 1H), 2.42 (s, 3H), 2.32-2.24 (m, 2H), 2.19-2. 08(m,2H),1.34(s,9H).

Step 2-4-[3-(tert-Butyloxycarbonylamino)cyclobutyl]piperazine-1-carboxylic acid benzyl ester

To a solution of [3-(tert-butoxycarbonylamino)cyclobutyl]4-methylbenzenesulfonate (2.80 g, 8.20 mmol) and benzyl piperazine-1-carboxylate (2.71 g, 12.3 mmol, 2.38 mL) in DMF (15 mL) was added DMAP (50.1 mg, 410 μmol). The mixture was stirred at 100 °C for 16 hr. Upon completion, the residue was diluted with water (60 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (20 mL) and _dried over _Na2SO4 , filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (2 g, 62% yield) as a brown oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.35(s,5H),5.13(s,2H),4.82-4.67(m,1H),3.97-3.79(m,1H),3.55(s,4H),2.58-2.31(m,6H),1.80-1.78(m,2H),1.43(s, 9H), LC-MS(ESI+)m/z 390.3(M+H) ⁺ .

Step 3-tert-Butyl N-(3-piperazin-1-ylcyclobutyl)carbamate

To a solution of benzyl 4-[3-(tert-butoxycarbonylamino)cyclobutyl]piperazine-1-carboxylate (500 mg, 1.28 mmol) in THF (10 mL) was added Pd/C (500 mg, 1.28 mmol, 10 wt%), and the reaction mixture was then stirred at 25 °C under _H2 for 1 hr. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (327 mg, 99% yield) as a white solid, LC-MS (ESI+) m/z 255.8 (M+H) ⁺ .

3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzene [[(1-( ...

Step 1-N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazole-5- tert-butyl]-4-piperidinyl]methyl]piperazin-1-yl]cyclobutyl]carbamate

To a solution of tert-butyl N-(3-piperazin-1-ylcyclobutyl)carbamate (293 mg, 1.15 mmol, intermediate JT) and 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidine-4-carbaldehyde (425 mg, 1.15 mmol, intermediate DM) in DMF (2 mL) and THF (10 mL) was added TEA (116 mg, 1.15 mmol, 159 μL). The mixture was stirred at -10 °C for 10 min, then AcOH (137 mg, 2.29 mmol, 131 μL) was added to the mixture, and the mixture was stirred at -10 °C for 20 min. Then NaBH(OAc) ₃ (316 mg, 1.49 mmol) was added to the mixture, and the mixture was stirred at -10 °C for 1 hr. After completion, the reaction mixture was quenched with water (0.5 mL) and concentrated in vacuo to give a residue. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (450 mg, 64% yield) as a purple solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.06 (s, 1H), 8.16 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.62 (dd, J=2.0, 8.4 Hz, 1H), 5.28 (dd, J=5.2, 13.2 Hz, 1H), 3.67-3.60 (m, 1H), 3.57-3.54 (m, 2H), 3.29 (s ,3H),2.95-2.83(m,1H),2.74-2.65(m,1H),2.64-2.52(m,4H),2.43-2.20(m,9H),2.18-2.16(m,2H),2.02-1.93(m,1H),1.78-1.75(m,2H),1.70 -1.56(m,3H),1.36(s,9H),1.30-1.15(m,2H), LC-MS(ESI ⁺ )m/z 610.4(M+H) ⁺ .

Step 2-3-[5-[4-[[4-(3-aminocyclobutyl)piperazin-1-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo [-Benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]cyclobutyl]carbamate (100 mg, 164 μmol) in DCM (1 mL) was added HCl/dioxane (3 M, 2 mL). The mixture was then stirred at 25 °C for 2 hr. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (89 mg, 99% yield, HCl) as a grey solid. LC-MS (ESI ⁺ ) m/z 510.4 (M+H) ⁺ .

3-[5-[4-(3,9-diazaspiro[5.5]undec-3-ylmethyl)-1-piperidinyl]-3-methyl-2-oxo-benzo [Imidazol-1-yl]piperidine-2,6-dione (Intermediate JV)

Step 1-9-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4- [piperidinyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester

To a solution of 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidine-4-carbaldehyde (210 mg, 567 μmol, intermediate DM) and tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (158 mg, 623 μmol, CAS# 173405-78-2) in THF (2 mL) and DMF (2 mL) was added HOAc (34.0 mg, 567 μmol) and TEA (57.3 mg, 567 μmol) at -10°C and the mixture was stirred at -10°C for 20 min. Then, NaBH(OAc) ₃ (180 mg, 850 μmol) was added at -10°C and the reaction mixture was stirred at -10°C for 2 hr. Upon completion, the reaction mixture was quenched with _H2O (0.5 mL). The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 3%-33%, 15min) to give the title compound (250mg, 72% yield) as a brown solid. ^1H NMR (400MHz, DMSO- _d6 ) δ11.05(s,1H),6.92(d, J=8.4Hz,1H),6.81(d, J=2.0Hz,1H),6.62(dd, J=2.0,8.4Hz,1H),5.28(dd, J=5.2,12.8Hz,1H),3.57(d, J=12.0Hz,2H),3.27(s,4H),2.95-2.83(m,1H),2.73-2. .58(m,4H),2.55-2.51(m,3H),2.38(d,J＝6.8Hz,2H),2.02-1.95(m,1H),1.78(d,J＝12.8Hz,2H),1.69(dd,J＝3.6,7.2Hz,1H),1.54-1.47(m,4H),1.40 -1.32(m,15H),1.32-1.19(m,4H).

Step 2-3-[5-[4-(3,9-diazaspiro[5.5]undec-3-ylmethyl)-1-piperidinyl]-3-methyl-2-oxo [-Benzimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl 9-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]methyl]-3,9-diazaspiro[5.5]undecane-3-carboxylate (100 mg, 164 μmol) in DCM (0.2 mL) was added HCl/dioxane (4 M, 1.00 mL) and the reaction mixture was then stirred at 25 °C for 1 hr. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (89 mg, 99% yield) as a yellow solid. LCMS (ESI ⁺ ) m/z 509.4 (M+H) ⁺ .

7-Bromoheptanal (Intermediate JW)

To a solution of 7-bromoheptan-1-ol (100 mg, 512 μmol, CAS# 10160-24-4) in DCM (3 mL) was added DMP (260 mg, 615 μmol). The mixture was stirred at 25 °C for _{1 hr. Upon completion, the reaction mixture was quenched with Na2S2O3 · 5H2O (} 10 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to give the title compound (95 mg, 95% yield) as a white solid.

3-(4-Amino-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (Intermediate JX)

Step 1-2-(Methylamino)-3-nitro-benzoic acid

To a solution of _MeNH2 /EtOH (54.0 mmol, 200 mL, 30% solution) was added 2-fluoro-3-nitro-benzoic acid (10.0 g, 54.0 mmol) portionwise at 0°C. The reaction mixture was then stirred at 20°C for 2 hr. Upon completion, the mixture was concentrated in vacuo. The residue was diluted with water (100 mL) and acidified to pH = 3-5 with citric acid, stirred and filtered. The filter cake was dried in vacuo to give the title compound (9.60 g, 91% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.41 (s, 1H), 8.62 (s, 1H), 8.04 (dd, J = 1.6, 8.0 Hz, 1H), 7.97 (dd, J = 1.6, 8.0 Hz, 1H), 6.72 (t, J = 8.0 Hz, 1H), 2.70 (s, 3H).

Step 2-3-Methyl-4-nitro-1H-benzimidazol-2-one

To a solution of 2-(methylamino)-3-nitro-benzoic acid (8.60 g, 43.8 mmol) and DIPEA (17.0 g, 132 mmol) in t-BuOH (200 mL) was added DPPA (12.1 g, 43.8 mmol) dropwise at 0°C. The reaction mixture was then stirred at 85°C for 12 h. Upon completion, the mixture was diluted with MeOH (100 mL), cooled to 10-20°C, filtered and the filter cake was dried under vacuum to give the title compound (6.80 g, 80% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO- _d6 ) δ 11.61 (s, 1H), 7.58 (dd, J = 0.8, 8.0 Hz, 1H), 7.30 (dd, J = 0.8, 8.0 Hz, 1H), 7.18-7.07 (m, 1H), 3.34 (s, 3H).

Step 3-1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzimidazol-1-yl)piperidin Pyridine-2,6-dione

To a solution of 3-methyl-4-nitro-1H-benzimidazol-2-one (7.20 g, 37.3 mmol) in THF (70 mL) was added t-BuOK (8.37 g, 74.6 mmol) at -10-0 ° C. After one hour, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (21.3 g, 55.9 mmol, intermediate H) in THF (50 mL) was added to the above mixture and the reaction mixture was stirred at 0-20 ° C for 12 hr. After completion, the mixture was acidified to pH = 3-5 with FA, diluted with water (300 mL), and extracted with EA (2 × 300 mL). The organic layer was washed with brine (200 mL) and then concentrated in vacuo. The residue was purified by reverse phase (0.1% FA condition) to give the title compound (5.80 g, 37% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.69 (dd, J＝0.8, 8.0Hz, 1H), 7.46 (d, J＝8.0Hz, 1H), 7.27-7.17 (m, 3H), 6.93-6.78 (m, 2H), 5.67 (dd, J＝5.2, 12.8Hz, 1H), 4.94-4. 62(m,2H),3.72(s,3H),3.41(s,3H),3.11-2.98(m,1H),2.89-2.70(m,2H),2.17-2.08(m,1H).

Step 4-3-(3-methyl-4-nitro-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione

To a solution of 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (2.00 g, 4.71 mmol) in TFA (20 mL) was added TfOH (2 mL). The reaction mixture was stirred at 60 ° C for 12 hours. After completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA conditions) to give the title compound (900 mg, 63% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.19(s,1H),7.68(dd,J＝0.8,8.0Hz,1H),7.55(d,J＝8.0Hz,1H),7.23(t,J＝8.0Hz,1H),5.51(dd,J＝5.2,12.8Hz,1H),3.41(s,3H) ,2.95-2.85(m,1H),2.80-2.60(m,2H),2.13-2.06(m,1H).

Step 5-3-(4-amino-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione

To a solution of 3-(3-methyl-4-nitro-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (850 mg, 2.79 mmol) in THF (50 mL) was added Pd/C (200 mg, 10% wt). The reaction mixture was stirred at 20° C. under H ₂ (15 Psi) atmosphere for 12 hr. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a pink solid (0.70 g, 91% yield). LC-MS (ESI ⁺ ) m/z 275.1 (M+H) ⁺ .

3-(4-amino-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2- 6-Diketone (Intermediate JY)

To a solution of 1-[(4-methoxyphenyl)methyl]-3-(3-methyl-4-nitro-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (310 mg, 730 μmol, intermediate JX) in a mixed solution of EtOH (5 mL) and H ₂ O (5 mL) were added Fe (203 mg, 3.65 mmol) and NH ₄ Cl (390 mg, 7.30 mmol). The mixture was stirred at 80° C. for 2 hr. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was then partitioned between EA (10 ml) and water (10 ml). The organic layer was collected, and the aqueous layer was extracted with EA (2×8 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (285 mg, 98% yield) as a yellow solid. LCMS(ESI ⁺ )m/z 394.9(M+H) ⁺ .

3-[4-(7-bromoheptylamino)-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl [4-(2-[4-(2-[4-(2-piperidin-2,6-dione)]]]

To a solution of 3-(4-amino-3-methyl-2-oxo-benzoimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (50.0 mg, 126 μmol, Intermediate JY) in a mixed solvent of THF (2 mL) and DMF (0.5 mL) was added 7-bromoheptanal (25.7 mg, 133 μmol, Intermediate JW) and tetraisopropoxytitanium (72.0 mg, 253 μmol) at 25° C. for 16 hr. Then, NaBH ₃ CN (15.9 mg, 253 μmol) was added to the mixture and the reaction mixture was stirred at 25° C. for 1 hr. The reaction mixture was partitioned between H ₂ O (20 mL) and EA (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-TLC (SiO ₂ , PE:EA=1:1) to give the title compound (25 mg, 34% yield) as a white solid. LCMS (ESI ⁺ ) m/z 573.1 (M+H) ⁺ .

6-Chloro-8-isopropyl-2-(4-piperidinylamino)pyrido[2,3-d]pyrimidin-7-one (Intermediate KA)

Step 1-4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]piperidin-1-yl Tert-butyl ester

To a solution of 6-chloro-8-isopropyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one (450 mg, 1.49 mmol, intermediate KP) in DMSO (1 mL) was added DIEA (192 mg, 1.49 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (358 mg, 1.79 mmol, CAS#502482-34-0). The mixture was stirred at 90 ° C for 1 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water (FA)-ACN]; B%: 65%-75%, 22min) to give the title compound (800 mg, 63% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.62-8.56(m,1H),8.05(s,1H),7.97(d,J＝7.2Hz,1H),7.81(d,J＝6.4Hz,1H),5.86-5.61(m,1H),4.09-3.98(m,1H),3.92(d, J＝12.4Hz,2H),2.97-2.82(m,2H),1.90-1.80(m,2H),1.54-1.48(m,6H),1.40(s,12H). LCMS(ESI ⁺ )m/z 422.0(M+H) ⁺ .

Step 2-6-Chloro-8-isopropyl-2-(4-piperidinylamino)pyrido[2,3-d]pyrimidin-7-one

To a solution of tert-butyl 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]piperidine-1-carboxylate (170 mg, 402 μmol) in DCM (3 mL) was added TFA (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated in vacuo to give the title compound (175 mg, 99% yield, TFA) as a white solid. LCMS (ESI ⁺ ) m/z 321.9 (M+H) ⁺ .

6-Chloro-8-isopropyl-2-[[1-(1H-pyrazol-4-ylsulfonyl)-4-piperidinyl]amino]pyrido[2,3-d] Pyrimidin-7-one (Intermediate KB)

To a solution of 6-chloro-8-isopropyl-2-(4-piperidinylamino)pyrido[2,3-d]pyrimidin-7-one (175 mg, 401 μmol, TFA, intermediate KA) in DMF (4 mL) was added DIEA (155 mg, 1.20 mmol) and 1H-pyrazole-4-sulfonyl chloride (93.6 mg, 562 μmol, CAS#438630-64-9). The mixture was stirred at 25 °C for 0.5 hr. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 9 min) to give the title compound (100 mg, 55% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ13.76 (s, 1H), 8.57 (s, 1H), 8.40-8.10 (m, 1H), 8.04 (s, 1H), 8.01 (d, J = 7.2Hz, 1H), 7.86 (d, J = 7.2Hz, 1H), 5.86-5.51 (m, 1H), 3. 81(d,J＝15.2Hz,1H),3.47(d,J＝12.0Hz,2H),2.49-2.46(m,1H),2.45-2.35(m,1H),2.03-1.89(m,2H),1.70-1.57(m,2H),1.48(d,J＝6.8Hz,6H). LCMS(ESI ⁺ )m/z 452.0(M+H) ⁺ .

6-(Difluoromethyl)-2-methanesulfonyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (intermediate KC)

Step 1-5-Bromo-2-methylsulfanyl-N-spiro[2.4]hept-7-yl-pyrimidin-4-amine

To a solution of 5-bromo-2-chloro-N-spiro[2.4]hept-7-yl-pyrimidin-4-amine (6.70 g, 22.1 mmol, synthesized via step 1 of intermediate HX) in DMF (70 mL) was added NaSMe (2.54 g, 36.2 mmol, 2.31 mL) at 0 °C. The reaction was stirred at 25 °C for 16 hr. Upon completion, the reaction was diluted with EA (150 mL). The organic layer was washed with water (2 x 100 mL), dried over _{anhydrous Na2SO4} and filtered. The filtrate was concentrated in vacuo to give the title compound (6.2 g, 89% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 315.8 (M+1) ⁺ .

Step 2-(E)-3-[2-methylsulfanyl-4-(spiro[2.4]hept-7-ylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester

To a solution of 5-bromo-2-methylsulfanyl-N-spiro[2.4]hept-7-yl-pyrimidin-4-amine (6.20 g, 19.7 mmol), TEA (2.00 g, 19.7 mmol, 2.75 mL) and Pd(PPh ₃ ) ₄ (2.28 g, 1.97 mmol) in DMF (100 mL) was added methyl prop-2-enoate (13.0 g, 151 mmol, 13.6 mL, CAS# 96-33-3). The reaction was then stirred at 90 °C under N ₂ for 32 hr. Upon completion, the reaction was diluted with EA (200 mL). The organic layer was washed with water (2×100 mL), dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo and the residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/4) to give the title compound (3.9 g, 61% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 320.3 (M+1) ⁺ .

Step 3-2-Methylsulfanyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one

To a solution of (E)-3-[2-methylsulfanyl-4-(spiro[2.4]hept-7-ylamino)pyrimidin-5-yl]prop-2-enoic acid methyl ester (2.80 g, 8.77 mmol) in NMP (30 mL) was added DBU (6.67 g, 43.8 mmol, 6.61 mL). The reaction was stirred at 150 °C under _N2 for 2 hr. Upon completion, the reaction was diluted with EA (300 mL). The organic layer was washed with water (3×100 mL), dried _over anhydrous _Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was then purified by column chromatography ( _SiO2 , petroleum ether/ethyl acetate=5/1) to give the title compound (2.3 g, 91% yield) as a brown solid. LC-MS (ESI ⁺ ) m/z 288.0 (M+1) ⁺ .

Step 4-6-[Chloro(difluoro)methyl]-2-methylsulfanyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidine- 7-Keto

To a 15 mL vial equipped with a stir bar was added a solution of 4-phenylpyridine N-oxide (2.38 g, 13.9 mmol), 2-methylsulfanyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 6.96 mmol), Ru(bpy) ₃ Cl ₂ .6H ₂ O (52.1 mg, 69.5 μmol) in anhydrous ACN (2 mL). (2-Chloro-2,2-difluoro-acetyl) 2-chloro-2,2-difluoro-acetate (4.23 g, 17.40 mmol, CAS# 2834-23-3) was then added. The vial was sealed and placed under added nitrogen. The reaction was stirred and irradiated with a 34W blue LED lamp (2 cm away) while the reaction temperature was maintained at 25° C. for 16 hr with cooling water. Upon completion, the reaction was concentrated in vacuo. The residue was then purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 3/1) to give the title compound (2.59 g, 100% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 372.0 (M+1) ⁺ .

Step 5-N-[5-isopropoxy-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-yl]ethyl Amide

A mixture of 6-[chloro(difluoro)methyl]-2-methylsulfanyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (1.00 g, 2.69 mmol), Pd/C (318 mg, 268 μmol, 10 wt%), Na ₂ CO ₃ (427 mg, 4.03 mmol) in THF (20 mL) was degassed and purged with H ₂ three times. The mixture was then stirred under H ₂ (30 Psi) at 25 °C for 1 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-HPLC (column: YMC Triart C18 250*50mm*7μm; mobile phase: [water(FA)-ACN]; B%: 60%-70%, 20 min) to give the title compound (107 mg, 11% yield). LC-MS(ESI ⁺ )m/z 338.0(M+1) ⁺ .

Step 6-6-(Difluoromethyl)-2-methanesulfonyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 6-(difluoromethyl)-2-methylsulfanyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 296 μmol) in DCM (2 mL) was added m-CPBA (240 mg, 1.19 mmol, 85% solution). The mixture was stirred at 40 °C for 16 hr. Upon completion, the reaction mixture was quenched with H ₂ O (5 mL) at 25 °C and then extracted with EA (3×5 mL). The combined organic layers were washed with brine (2×5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was then purified by prep-TLC (SiO ₂ , PE:EA=1:1) to give the title compound (50 mg, 40% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ9.04(s,1H),8.07(s,1H),7.02-6.69(m,1H),6.01-5.69(m,1H),3.40(s,3H),2.59-2.49(m,1H),2.25-2.13(m,2H),1.97-1.8 5(m,1H),1.56(s,1H),1.47-1.42(m,1H),0.75-0.59(m,3H),0.03-0.01(m,1H). LC-MS(ESI ⁺ )m/z 370.0(M+1) ⁺ .

4-[[6-(Difluoromethyl)-7-oxo-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-2-yl]amino [Methyl]-3-methyl-benzenesulfonyl chloride (Intermediate KD)

Step 1-2-(4-Benzylthio-2-methyl-phenylamino)-6-(difluoromethyl)-8-spiro[2.4]hept-7-yl-pyrrolidone Imido[2,3-d]pyrimidin-7-one

A mixture of 6-(difluoromethyl)-2-methanesulfonyl-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (45.0 mg, 121 μmol, intermediate KC), 4-benzylsulfanyl-2-methyl-aniline (83.8 mg, 365 μmol, intermediate DE) and TFA (138 mg, 1.22 mmol, 90.2 μL) in IPA (2 mL) was stirred at 90 °C for 32 hr. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was then purified by prep-TLC (SiO ₂ , PE:EA=1:1) to give the title compound (35 mg, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 519.4 (M+1) ⁺ .

Step 2-4-[[6-(Difluoromethyl)-7-oxo-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidine-2- 1-Methyl-1-amino-3-methyl-benzenesulfonyl chloride

To a solution of 2-(4-benzylsulfanyl-2-methyl-phenylamino)-6-(difluoromethyl)-8-spiro[2.4]hept-7-yl-pyrido[2,3-d]pyrimidin-7-one (26.9 mg, 51.9 μmol2) in H ₂ O (0.06 mL), ACN (1 mL) and AcOH (0.1 mL) was added NCS (17.3 mg, 129 μmol). The mixture was stirred at 25° C. for 0.5 hr. Upon completion, the reaction mixture was quenched with H ₂ O (10 mL) at 25° C. and then extracted with EA (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was then purified by prep-TLC (SiO ₂ , PE/EA=1/1) to give the title compound (20 mg, 77% yield) as a white solid. LC-MS(ESI ⁺ )m/z 495.1(M+1) ⁺ .

4-Bromo-5-methoxy-3-methyl-1H-benzimidazol-2-one (Intermediate KE)

Step 1-2-Bromo-3-fluoro-1-methoxy-4-nitro-benzene

To a mixture of 2-bromo-1,3-difluoro-4-nitro-benzene (5.00 g, 21.01 mmol from CAS# 103977-78-2) in MeOH (50 mL) was added NaOMe (1.14 g, 21.0 mmol) at 0°C. The mixture was warmed to 20°C and stirred for 2 hours. Upon completion, the mixture was poured into water (60 mL) and the aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phases were washed with brine (2×40 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the crude product. The crude product was triturated with PE:EA=20:1 (10 mL) to give the title compound (1.80 g, 34% yield) as a white solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.14 (dd, J = 8.4, 9.2 Hz, 1H), 6.81 (dd, J = 1.6, 9.2 Hz, 1H), 4.04 (s, 3H).

Step 2-2-Bromo-3-methoxy-N-methyl-6-nitro-aniline

To a mixture of 2-bromo-3-fluoro-1-methoxy-4-nitro-benzene (1.60 g, 6.40 mmol) in THF (20 mL) was added MeNH ₂ (2M, 4.80 mL), and the mixture was stirred at 20° C. for 2 hours. After completion, the mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50:1 to 10:1) to give the title compound (1.40 g, 83% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, J=9.6 Hz, 1 H), 6.73 (s, 1 H), 6.44 (d, J=9.2 Hz, 1 H), 3.97 (s, 3 H), 3.09 (d, J=5.2 Hz, 3 H).

Step 3-3-Bromo-4-methoxy-N2-methyl-benzene-1,2-diamine

To a mixture of 2-bromo- ₃ -methoxy-N-methyl-6-nitro-aniline (1.40 g, 5.36 mmol) in THF (10 mL) and MeOH (10 mL) was added platinum (104 mg, 53.6 μmol, 10 wt%) under H2 (15 psi) and stirred at 20 °C for 2 h. After completion, the mixture was filtered and concentrated to give the title compound (1.20 g, 96% yield) as a yellow solid.

Step 4-4-Bromo-5-methoxy-3-methyl-1H-benzimidazol-2-one

To a mixture of 3-bromo-4-methoxy-N2-methyl-benzene-1,2-diamine (1.1 g, 4.76 mmol) in CH ₃ CN (20 mL) was added CDI (1.16 g, 7.14 mmol) and the mixture was stirred at 90° C. for 3 hours. Upon completion, the mixture was concentrated to remove CH ₃ CN and then H ₂ O (10 mL) was added to the mixture. The mixture was filtered to get a filter cake which was dried to afford the title compound (1.00 g, 81% yield) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.89 (d, J=8.4 Hz, 1 H), 6.59 (d, J=8.8 Hz, 1 H), 3.81 (s, 3 H), 3.71 (s, 3 H), 2.72 (d, J=2.4 Hz, 1 H).

Step 5-4-Bromo-5-methoxy-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo [d]Imidazol-2(3H)-one

To a solution of 7-bromo-6-methoxy-1-methyl-1H-benzo[d]imidazol-2(3H)-one (1.00 g, 3.90 mmol) in THF (30 mL) was added NaH (234 mg, 5.85 mmol, 60% dispersion in mineral oil) at 0°C, and the mixture was stirred at 0°C for 0.5 hr. Then SEM-Cl (0.98 g, 5.85 mmol) was added to the above solution and the mixture was stirred at 65°C for 10 hr. After completion, the mixture was quenched with _H2O (30 mL) and extracted with EA (2×30 mL). The organic layer was washed with brine (2×30 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The mixture was purified by silica gel column (PE:EA=20:1) to give the title compound (1.30 g, 86% yield) as a yellow oil. LC-MS(ESI ⁺ )m/z 387.0(M+H) ⁺ .

3-(5-methoxy-3-methyl-4-(4-(methylamino)piperidin-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d] Imidazol-1-yl)piperidine-2,6-dione (Intermediate KF)

Step 1-N-[1-[5-methoxy-3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazole [4-oxazol-4-yl]-4-piperidinyl]-N-methyl-carbamic acid tert-butyl ester

A solution of 4-bromo-5-methoxy-3-methyl-1-(2-trimethylsilylethoxymethyl)benzimidazol-2-one (250 mg, 645 μmol, intermediate KE), tert-butyl N-methyl-N-(4-piperidinyl)carbamate (276 mg, 1.29 mmol, CAS# 108612-54-0), (t-Bu)PhCPhos Pd G4 (35 mg, 64.5 μmol) and t-BuOK (217 mg, 1.94 mmol) in dioxane (8 mL) was stirred at 85 °C under _N2 for 16 hr. Upon completion, the reaction mixture was diluted with EtOAC (40 mL) and washed with _brine (2 x 20 mL). The organic layer was separated and dried over _Na2SO4 and concentrated in vacuo. The residue was purified by reverse phase (FA conditions) to give the title compound (35.0 mg, 10% yield). ¹ H NMR (400MHz, MeOD) δ7.04(d,J＝8.8Hz,1H),6.79(d,J＝8.8Hz,1H),5.31(s,2H),3.89(s,3H),3.81(s,3H),3.67-3.53(m,4H),3.39(s,1H),3.06-2.99( m,2H),2.87(s,3H),2.09-1.92(m,2H),1.68(d,J=12Hz,2H),1.53(s,9H),1.39-1.31(m,2H),0.98-0.89(m,2H),0.00(s,9H).

Step 2-(1-(5-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl tert-Butyl (methyl)carbamate

To a solution of tert-butyl N-[1-[5-methoxy-3-methyl-2-oxo-1-(2-trimethylsilylethoxymethyl)benzimidazol-4-yl]-4-piperidinyl]-N-methyl-carbamate (40.0 mg, 76.8 μmol) in THF (5 mL) at 25° C. was added TBAF (200 mg, 768 μmol). The reaction was warmed to 70° C. and stirred for 16 hr. Upon completion, the reaction mixture was diluted with EtOAc (60 mL) and washed with brine (4×30 mL). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (29.0 mg, 96% yield) as a brown solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.78(d,J＝8.4Hz,1H),6.67(d,J＝8.4Hz,1H),3.82(s,3H),3.61(s,3H),3.38-3.20(m,2H),3.01-2.90(m,2H),2.79(s,3H),1 .97-1.82(m,2H),1.64-1.51(m,2H),1.48(s,9H).

Step 3-(1-(5-methoxy-1-(1-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl- tert-Butyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)(methyl)carbamate

To a solution of tert-butyl N-[1-(5-methoxy-3-methyl-2-oxo-1H-benzimidazol-4-yl)-4-piperidinyl]-N-methyl-carbamate (24.0 mg, 61.4 μmol) in THF (3 mL) was added tBuOK (13.8 mg, 122 μmol) at 0°C, and the mixture was stirred at 0°C for 30 min. Subsequently, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]trifluoromethanesulfonate (37.5 mg, 98.3 μmol, Intermediate G) in THF (0.5 mL) was slowly added to the mixture, and the reactants were stirred at 0°C for 2 hr. Upon completion, the reaction mixture was quenched with saturated NH ₄ Cl solution (1 mL) and diluted with water (10 mL). The mixture was then extracted with EtOAc (2×40 mL). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by prep-TLC (DCM:EtOAc=3:1, Rf=0.5) to give the title compound (36 mg, 94% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 622.2 (M+H) ⁺ .

Step 4-3-(5-methoxy-3-methyl-4-(4-(methylamino)piperidin-1-yl)-2-oxo-2,3-dihydro-1H- Benz[d]imidazol-1-yl)piperidine-2,6-dione

To a solution of tert-butyl N-[1-[5-methoxy-1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidinyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidinyl]-N-methyl-carbamate (30.0 mg, 48.2 μmol) in TFA (0.4 mL) was added TfOH (0.08 mL) at 25 °C. The reaction mixture was warmed to 70 °C and stirred for 3 hr. After completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 3%-33%, 11 min) to give the title compound (11.0 mg, 56% yield) as a white solid. LC-MS(ESI ⁺ )m/z 402.1(M+H) ⁺ .

3-[5-methoxy-3-methyl-4-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]-2-oxo-benzene [[(1-( ...

Step 1-4-[[[1-[1-(2,6-dioxo-3-piperidinyl)-5-methoxy-3-methyl-2-oxo-benzimidazole [4-oxazol-4-yl]-4-piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylic acid tert-butyl ester

To a solution of 3-[5-methoxy-3-methyl-4-[4-(methylamino)-1-piperidinyl]-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (110 mg, 213 μmol, TFA, intermediate KF) in THF (1 mL) was added TEA (59.4 μL, 426 μmol). Then tert-butyl 4-formylpiperidine-1-carboxylate (40.9 mg, 192 μmol, CAS# 137076-22-3) and HOAc (12.2 μL, 213 μmol) were added and the mixture was stirred at -10 °C for 0.5 hours. Then NaBH(OAc) ₃ (67.8 mg, 320 μmol) was added and the mixture was stirred at -10 °C for 1.5 hr. Upon completion, the mixture was quenched with water (1 mL), filtered and the filtrate concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 10%-40%, 10 min) to give the title compound (80.0 mg, 62% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.06 (s, 1H), 6.87 (d, J = 8.4Hz, 1H), 6.68 (d, J = 8.8Hz, 1H), 5.32-5.27 (m, 1H), 3.96-3.93 (m, 2H), 3.77 (s, 3H), 3.60 (s, 3H), 3. 38-3.33(m,2H),2.99-2.97(m,2H),2.93-2.81(m,2H),2.78-2.57(m,7H),2.53-2.51(m,2H),2.01-1.66(m,8H),1.40(s,9H),1.11-0.95(m,2H). LC-MS(ESI ⁺ )m/z 599.2(M+H) ⁺ .

Step 2-3-[5-methoxy-3-methyl-4-[4-[methyl(4-piperidinylmethyl)amino]-1-piperidinyl]-2-oxo [-Benzimidazol-1-yl]piperidine-2,6-dione

A solution of tert-butyl 4-[[[1-[1-(2,6-dioxo-3-piperidinyl)-5-methoxy-3-methyl-2-oxo-benzoimidazol-4-yl]-4-piperidinyl]-methyl-amino]methyl]piperidine-1-carboxylate (50.0 mg, 83.4 μmol) in HCl/dioxane (1 mL) was stirred at 25° C. for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (40.0 mg, 89% yield, HCl) as a yellow solid. LC-MS (ESI ⁺ ) m/z 499.1 (M+H) ⁺ .

3-[5-[4-[[4-(3-aminopropyl)piperazin-1-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo-benzimidazole [1-oxazol-1-yl]piperidine-2,6-dione (Intermediate KH)

Step 1-N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazole-5- tert-butyl]-4-piperidinyl]methyl]piperazin-1-yl]propyl]carbamate

To a solution of tert-butyl N-(3-piperazin-1-ylpropyl)carbamate (50.0 mg, 205 μmol, CAS# 874831-60-4) and 1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]piperidine-4-carbaldehyde (85.5 mg, 205 μmol, FA, intermediate DM) in a mixed solvent of THF (1 mL) and DMF (1 mL) was added KOAc (201 mg, 2.05 mmol). The mixture was stirred at 0°C for 5 min. Then NaBH(OAc) ₃ (87.0 mg, 410 μmol) was added, and the mixture was stirred at 0°C for 30 min. Upon completion, the mixture was quenched with _H2O (0.5 mL) and then concentrated in vacuo to get a residue. The residue was purified by pre-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; B%: 0%-23%, 9 min) to give the title compound (88 mg, 71% yield) as a colorless oily liquid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.05 (s, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.85-6.76 (m, 2H), 6.62 (dd, J=1.6, 8.4 Hz, 1H), 5.28 (dd, J=5.2, 12.8 Hz, 2H), 3.57 (d, J=11.6 Hz, 8H), 2.96-2.88 (m, 6H), 2.74- 2.70(m,2H),2.42(s,3H),2.33(t,J＝7.2Hz,3H),2.19(d,J＝7.2Hz,2H),2.01-1.94(m,1H),1.78(d,J＝11.2Hz,2H),1.57-1.50(m,2H),1.37(s,9H),1. 29-1.18(m,2H). LC-MS(ESI ⁺ )m/z 598.2(M+H) ⁺ .

Step 2-3-[5-[4-[[4-(3-aminopropyl)piperazin-1-yl]methyl]-1-piperidinyl]-3-methyl-2-oxo- [benzoimidazol-1-yl]piperidine-2,6-dione

To a solution of tert-butyl N-[3-[4-[[1-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]-4-piperidinyl]methyl]piperazin-1-yl]propyl]carbamate (60.0 mg, 100 μmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at 25 °C for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound (45.0 mg, 90% yield) as a colorless oily liquid. LC-MS (ESI ⁺ ) m/z 498.1 (M+H) ⁺ .

Tributyl-(3-isopropyl-2-methyl-imidazol-4-yl)stannane (Intermediate KI)

Step 1-5-Bromo-1-isopropyl-2-methyl-imidazole and 4-Bromo-1-isopropyl-2-methyl-imidazole

To a mixture of 1-isopropyl-2-methyl-imidazole (10.0 g, 80.5 mmol, CAS# 87606-45-1) in ACN (100 mL) was added NBS (14.3 g, 80.5 mmol) at 0° C., and then the reaction mixture was stirred for 16 hours at 25° C. After completion, the residue was diluted with water (80 mL) and extracted with EA (3×100 mL). _The combined organic layers were dried over _Na2SO4 , filtered and concentrated in vacuo to afford 5-bromo-1-isopropyl-2-methyl-imidazole (8.00 g, 49% yield, ^1H NMR (400 MHz, DMSO- _d6 ) δ 6.79 (s, 1H), 4.57 (d, J = 7.0, 14.0 Hz, 1H), 2.37 (s, 3H), 1.46 (d, J = 7.2 Hz, 6H) and 4-bromo-1-isopropyl-2-methyl-imidazole (2.00 g, 12% yield, ^1H NMR (400 MHz, DMSO- _d6) δ 7.79 (s, 1H), 4.57 (d, J = 7.0, 14.0 Hz, 1H), 2.37 (s, 3H), 1.46 (d, J = 7.2 Hz, 6H) as a white oil. )δ=7.29(s,1H),4.34(td,J=6.4,13.2Hz,1H),2.27(s,3H),1.32(d,J=6.4Hz,6H).

Step 2 – Tributyl-(3-isopropyl-2-methyl-imidazol-4-yl)stannane

To a mixture of 5-bromo-1-isopropyl-2-methyl-imidazole (1.50 g, 7.39 mmol) in dioxane (30 mL) was added Pd ₂ (dba) ₃ (676 mg, 738 μmol) and LiCl (939 mg, 22.1 mmol) and tricyclohexylphosphane (2.07 g, 7.39 mmol) and tributyl(tributylstannyl)stannane (42.8 g, 73.8 mmol), then the reaction mixture was stirred at 100° C. for 12 hr. Upon completion, the reaction mixture was quenched with CsF (aq) (50 mL) and concentrated in vacuo to give the title compound (3 g, 98% yield) as a brown oil. LC-MS (ESI ⁺ ) m/z 412.6 (M+H) ⁺ .

4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-3-methyl- Benzenesulfonyl chloride (Intermediate KJ)

Step 1-N-(4-Benzylthio-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)-5- (Trifluoromethyl)-pyrimidin-2-amine

To a mixture of tributyl-(3-isopropyl-2-methyl-imidazol-4-yl)stannane (3.00 g, 7.26 mmol, intermediate KI) and N-(4-benzylsulfanyl-2-methyl-phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (2.98 g, 7.26 mmol, intermediate EA) in dioxane (2 mL) was added K ₂ CO ₃ (3.01 g, 21.7 mmol), CuI (138 mg, 725 μmol) and Pd(PPh ₃ ) ₂ Cl ₂ (509 mg, 725 μmol). The reaction mixture was then stirred at 110° C. for 12 hr. Upon completion, the residue was diluted with water (30 mL) and extracted with EA (3×60 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=50:1 to PE:EA=1:1). The residue was then purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 27%-57%, 10min) to give the title compound (2 g, 55% yield) as a white solid. LC-MS (ESI ⁺ ) m/z 498.4 (M+H) ⁺ .

Step 2-4-[[4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]- 3-Methyl-benzenesulfonyl chloride

To a mixture of N-(4-benzylsulfanyl-2-methyl-phenyl)-4-(3-isopropyl-2-methyl-imidazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (65.0 mg, 130 μmol) in ACN (1 mL), HOAc (0.3 mL) and H ₂ O (0.1 mL) was added NCS (52.3 mg, 391 μmol). The reaction mixture was then stirred at 25° C. for 0.5 h. Upon completion, the mixture was concentrated in vacuo to give the title compound (60 mg, 86.0% yield, HOAC) as a yellow oil. LC-MS (ESI ⁺ ) m/z 474.2 (M+H) ⁺ .

3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6- Diketone (Intermediate KL)

Step 1-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole tert-Butyl oxazol-4-yl)-5,6-dihydropyridine-1(2H)-carboxylate

To a solution of 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (9.00 g, 26.6 mmol, Intermediate H), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (12.3 g, 39.9 mmol, CAS# 286961-14-6) and XPhos-Pd-G2 (2.09 g, 2.66 mmol) in dioxane (150 mL) and H ₂ O (15 mL) was added K ₃ PO ₄ (11.3 g, 53.2 mmol). The reaction mixture was stirred at 80 °C under N ₂ for 4 h. After completion, the reaction mixture was filtered. The filtrate was dried over anhydrous Na ₂ SO ₄ and filtered. The filtrate was concentrated in vacuo. The residue was triturated with saturated NH ₄ Cl (2×50 mL), water (2×50 mL) and EA (2×50 mL) and filtered. The solid was dried in vacuo to give the title compound as an off-white solid (8.00 g, 68% yield). LC-MS (ESI ⁺ ) m/z 441.1 (M+H) ⁺

Step 2-4-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole tert-Butyl oxazol-4-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (8.00 g, 18.2 mmol) in DMF (20 mL) and THF (60 mL) was added H ₂ , Pd/C (1.00 g, 10 wt %) and Pd(OH) ₂ (1.00 g, 3.56 mmol, 50 wt %). The mixture was degassed and purged with nitrogen 3 times, then degassed and purged with hydrogen 3 times. The mixture was stirred at 25 °C under hydrogen (15 psi) atmosphere for 16 hr. Upon completion, the reaction mixture was filtered and the combined filtrate was concentrated in vacuo to give the title compound (5.60 g, 70% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.10(s,1H),7.06-6.92(m,3H),5.38(m,1H),4.18-3.96(m,2H),3.60(s,3H),3.48-3.39(m,1H),2.97-2.81(m,3H),2.76 -2.61(m,2H),2.05-1.94(m,1H),1.81(m,2H),1.65-1.50(m,2H),1.47-1.40(m,9H). LC-MS(ESI ⁺ )m/z 287.4(387.3) ⁺ .

Step 3-3-(3-methyl-2-oxo-4-(piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2 Pyridine-2,6-dione

To a solution of tert-butyl 4-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-4-yl]piperidine-1-carboxylate (100 mg, 226 μmol) in DCM (1 mL) was added HCl/dioxane (1 mL). The reaction mixture was stirred at 25 °C for 0.5 h. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (85.0 mg, 99% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 343.3 (M+H) ⁺ .

6-Chloro-8-cyclopentyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate KM)

Step 1-8-Cyclopentyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.00 g, 7.65 mmol, intermediate HN) in DCM (20 mL) was added m-CPBA (6.21 g, 30.6 mmol, 85% solution). The mixture was stirred at 40 °C for 3 hr. Upon completion, the reaction mixture was quenched with aqueous Na ₂ CO ₃ solution (10 mL) at 25 °C and then extracted with EA (3×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (2.00 g, 89% yield) as a yellow oil. LC-MS (ESI ⁺ ) m/z 293.9 (M+1) ⁺ .

Step 2-6-Chloro-8-cyclopentyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-cyclopentyl-2-methanesulfonyl-pyrido [2,3-d] pyrimidin-7-one (100 mg, 340.9 μmol) in DMF (1 mL) was added NCS (500 mg, 3.75 mmol). The mixture was stirred at 70 ° C for 16 hr. After completion, the reaction mixture was filtered and concentrated in vacuo to give a residue. The crude product was then purified by reverse phase HPLC (0.1% FA conditions) to give the title compound (280 mg, 24% yield) as a brown solid. LC-MS (ESI ⁺ ) m / z 327.9 (M + 1) ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.94(s,1H),7.96(s,1H),6.08-5.92(m,1H),3.40(s,3H),2.32-2.23(m,2H),2.22-2.13(m,2H),2.04-1.96(m,2H),1.77-1.70 (m,2H).

6-Chloro-8-cyclopentyl-2-[2-methyl-4-(2-oxopiperazin-1-yl)phenylamino]pyrido[2,3-d]pyrimidine- 7-Keto (Intermediate KN)

Step 1-4-(4-amino-3-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (2.00 g, 9.99 mmol, CAS#76003-29-7) and 4-iodo-2-methyl-aniline (2.79 g, 11.9 mmol, CAS#13194-68-8) in dioxane (35 mL) was added CuI (1.90 g, 9.99 mmol), K ₃ PO ₄ (5.30 g, 24.9 mmol) and N ₁ ,N ₂ -dimethylcyclohexane-1,2-diamine (2.84 g, 19.9 mmol). The mixture was then purged with N ₂ three times and stirred at 110 °C for 10 hr. Upon completion, the mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , PE:EA=10:1 to 1:5) to give the title compound (2.50 g, 81% yield) as a yellow solid. ² _.03 (s,3H),1.44(s,9H). LC-MS(ESI ⁺ )m/z 306.0(M+H) ⁺ .

Step 2-4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl [3-(4-(4-phenyl)-3-oxo-piperazine-1-carboxylic acid tert-butyl ester]

To a solution of 4-(4-amino-3-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.31 mmol) and 6-chloro-8-cyclopentyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one (429 mg, 1.31 mmol, intermediate KM) in dioxane (10 mL) was added Cs ₂ CO ₃ (853 mg, 2.62 mmol) and Pd-PEPPSI-IHeptCl 3-chloropyridine (127 mg, 130 μmol). The mixture was then purged with N ₂ three times and stirred at 80 °C for 12 hr. After completion, the mixture was filtered to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 55%-85%, 10 min) to give the title compound (85.0 mg, 11% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 553.3 (M+H) ⁺ .

Step 3-6-Chloro-8-cyclopentyl-2-[2-methyl-4-(2-oxopiperazin-1-yl)phenylamino]pyrido[2,3-d] Pyrimidin-7-one

To a solution of 4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-phenyl]-3-oxo-piperazine-1-carboxylic acid tert-butyl ester (80.0 mg, 144 μmol) was added HCl/dioxane (2 mL) and the mixture was then stirred at 25° C. for 1 hr. Upon completion, the mixture was concentrated in vacuo to give the title compound as a white solid (70.0 mg, 98% yield, HCl). LC-MS (ESI ⁺ ) m/z 452.9 (M+H) ⁺ .

4-[4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-benzene [3-Oxo-piperazin-1-yl]cyclohexanecarboxaldehyde (Intermediate KO)

Step 1-6-chloro-8-cyclopentyl-2-[4-[4-[4-(hydroxymethyl)cyclohexyl]-2-oxo-piperazin-1-yl]-2-methyl [2,3-d]pyrimidin-7-one

To a solution of 6-chloro-8-cyclopentyl-2-[2-methyl-4-(2-oxopiperazin-1-yl)phenylamino]pyrido[2,3-d]pyrimidin-7-one (70.0 mg, 154 μmol, HCl, intermediate KN) in DMF (0.5 mL) and THF (1 mL) was added TEA (718.45 μmol, 0.1 mL). Then 4-(hydroxymethyl)cyclohexanone (29.7 mg, 231 μmol, CAS#38580-68-6) and AcOH (1.75 mmol, 0.1 mL) were added and the mixture was stirred at 25° C. for 0.2 hours. Then NaBH(OAc) ₃ (65.5 mg, 309 μmol) was added and the mixture was stirred at 25° C. for 1 hr. After completion, the mixture was filtered to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water(FA)-ACN]; B%: 10%-40%, 15 min) to give the title compound (55.0 mg, 62% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.49(s,1H),8.70(s,1H),8.20-8.10(m,1H),7.41-7.33(m,1H),7.29-7.10(m,2H),5.81-5.62(m,1H),4.33(s,1H),3.66-3. 56(m,2H),3.28(s,2H),3.22(s,2H),2.89-2.80(m,2H),2.20(s,3H),2.17 -2.06(m,2H),1.91-1.77(m,2H),1.72-1.15(m,12H),0.97-0.84(m,1H),LC -MS(ESI ⁺ )m/z 565.2(M+H) ⁺ .

Step 2-4-[4-[4-[(6-chloro-8-cyclopentyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3- Methyl-phenyl]-3-oxo-piperazin-1-yl]cyclohexanecarboxaldehyde

To a solution of 6-chloro-8-cyclopentyl-2-[4-[4-[4-(hydroxymethyl)cyclohexyl]-2-oxo-piperazin-1-yl]-2-methyl-phenylamino]pyrido[2,3-d]pyrimidin-7-one (50.0 mg, 88.4 μmol) in DCM (1.5 mL) at 0°C was added DMP (56.2 mg, 132 μmol), and then the mixture was stirred at 25°C for 1 hr. Upon completion, the mixture was diluted with DCM (2 mL), then quenched with saturated Na ₂ S ₂ O ₃ (3 mL) and saturated NaHCO ₃ (3 mL), and stirred at 25°C for 10 minutes. After that, the mixture was extracted with DCM (3 mL×3). The combined organic layers were then dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (47.0 mg, 94% yield) as a yellow solid. LC-MS(ESI ⁺ )m/z 563.3(M+H) ⁺ .

6-Chloro-8-isopropyl-2-methylsulfonyl-pyrido[2,3-d]pyrimidin-7-one (Intermediate KP)

Step 1-8-Isopropyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-isopropyl-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-one (2.20 g, 9.35 mmol, intermediate DN) in DCM (20.0 mL) was added m-CPBA (7.59 g, 37.0 mmol, 85% solution). The mixture was stirred at 40 °C for 3 hr. Upon completion, the reaction mixture was quenched with aqueous Na ₂ CO ₃ solution (100 mL) at 25 °C and then extracted with EA (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (2.10 g, 84% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.27 (s, 1H), 8.07 (d, J = 9.6 Hz, 1H), 6.87 (d, J = 9.6 Hz, 1H), 5.65 (td, J = 6.8, 13.6 Hz, 1H), 3.46 (s, 3H), 1.56 (d, J = 7.2 Hz, 6H). LC-MS(ESI ⁺ )m/z 267.9(M+H) ⁺ .

Step 2-6-Chloro-8-isopropyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one

To a solution of 8-isopropyl-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-7-one (100 mg, 374 μmol) in DMF (1.50 mL) was added NCS (149 mg, 1.12 mmol). The mixture was stirred at 70 °C for 16 hr. After completion, the mixture was concentrated in vacuo. The mixture was purified by reverse phase (0.1% FA) to give the title compound (74.0 mg, 65% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.27-9.25 (m, 1H), 8.68-8.37 (m, 1H), 5.90-5.58 (m, 1H), 3.48 (d, J=2.4 Hz, 3H), 1.58 (s, 6H). LC-MS (ESI ⁺ ) m/z 301.8 (M+H) ⁺ .

1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde (Intermediate KQ)

Step 1-3-(3-methyl-2-oxo-5-vinyl-benzimidazol-1-yl)piperidine-2,6-dione

A mixture of 3-(5-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (3.00 g, 8.87 mmol, Intermediate J), potassium hydride, trifluoro(vinyl)boron (3.57 g, 26.6 mmol), Cs ₂ CO ₃ (2M, 8.87 mL), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (724 mg, 887 μmol) and in dioxane (30 mL) was degassed and purged with N ₂ three times, and then the mixture was stirred at 80 ° C under N ₂ atmosphere for 3 hours. After completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by reverse phase (TFA conditions) to give the title compound (1.60 g, 58% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 286.0 (M+H) ⁺ .

Step 2-1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazole-5-carbaldehyde

To a solution of 3-(3-methyl-2-oxo-5-vinyl-benzoimidazol-1-yl)piperidine-2,6-dione (0.30 g, 1.05 mmol) in a mixed solvent of dioxane (20 mL) and H ₂ O (2 mL) were added NaIO ₄ (449 mg, 2.10 mmol), OsO ₄ (267 mg, 1.00 mmol) and NMO (61.0 mg, 525 μmol). The mixture was stirred at 25 °C for 0.5 hr. After completion, the residue was diluted with water (10 mL) and extracted with ethyl acetate (2×20 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (TFA condition) to give the title compound (0.1 g, 32% yield) as a grey solid. LC-MS(ESI+)m/z 288.0(M+H) ⁺ .

Example 1 (Method 1): Synthesis of 2-((5-bromo-2-((4-(N-(15-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-3,6,9,12-tetraoxapentadecayl)sulfamoyl)-2-methylphenyl)amino)pyrimidin-4-yl)amino)-6-fluorobenzamide (I-37)

To a solution of 3-(4-(1-amino-3,6,9,12-tetraoxapentac-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione hydrochloride (51.3 mg, 0.097 mmol, intermediate D1) in DCM (5.0 mL) was added _Et3N (0.2 mL) and 4-((5-bromo-4-((2-carbamoyl-3-fluorophenyl)amino)pyrimidin-2-yl)amino)-3-methylbenzenesulfonyl chloride (50 mg, 0.097 mmol, intermediate L3) and the mixture was stirred at rt for 4 h. The mixture was diluted with water (15 mL) and extracted with DCM (30 mL x 3). _The combined organic extracts were dried over _Na2SO4 and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM/MeOH=10/1, v/v) to give the title compound (25.5 mg, 27% yield) as a white solid. LCMS m/z=970.4 & 972.4 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ11.1 (s, 1H), 10.2 (s, 1H), 9.00 (s, 1H), 8.28 (s, 1H), 8.18-8.03 (m, 3H), 7.73 (d, J=8.4 Hz, 1H), 7.67-7.54 (m, 3H), 7.32-7.23 (m, 1H), 7.02-6.92 (m, 3H), 6.91-6. 83(m,1H),5.35(dd,J＝12.4,5.4Hz,1H),3.55(s,3H),3.53-3.39(m,16H),2.97-2.84(m,5H),2.73-2.57(m,2H),2.29(s,3H),2.03-1.95(m,1H),1. 86-1.76(m,2H).

Table 4. Compounds synthesized by coupling the corresponding amines with benzenesulfonyl chloride via method 1.

^a The reaction was run at rt at any time from 1-24 hr. The coupled product was purified via standard techniques including prep-HPLC and reverse phase chromatography. ^b LCMS m/z is reported as [MH] ^- . ^c LCMS m/z is reported as [MH ₂ O+H] ⁺ . ^d LCMS m/z is reported as [M+Na] ⁺ . ^e DIEA was used as the base in ACN and the reaction was run at rt for 10 min to 2 hr. ^f The coupled product was then hydrogenated over Pd/C with DIEA or TEA in THF at rt under a hydrogen atmosphere for 0.5-40 h. ^g 2-Me-THF was used as solvent and the reaction was stirred at rt overnight.

Example 2 (Method 2): Synthesis of 3-(4-(1-(4-((6-(difluoromethyl)-8-((1R,2R)-2-hydroxy-2-methylcyclopentyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)-1-oxo-3,6,9,12-tetraoxapentadeca-15-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (I-21)

To a solution of 6-(difluoromethyl)-8-((lR,2R)-2-hydroxy-2-methylcyclopentyl)-2-(piperidin-4-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (55.8 mg, 0.142 mmol, Intermediate L1) and 15-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3,6,9,12-tetraoxopentadecanoic acid (60 mg, 0.118 mmol, Intermediate A1) in DMF (5 mL) was added _Et3N (119.4 mg, 1.18 mmol), and the mixture was cooled to -20 °C. Subsequently, a 50% solution of T ₃ P in DMF (90.1 mg, 0.142 mmol) was added and the mixture was stirred at -20°C for 2 h, then warmed to rt and stirred overnight. Upon completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC (model: SHIMADZU preparative HPLC system—including LC-20AP pump, SPD-20A detector and Labsolutions (version 5.90) software; column: Agilent 10, Prep-C18, 250×21.2 mm. Solvent/gradient: 5-80% acetonitrile/water (containing 0.1% HCOOH). Flow rate: 20 mL/min) to give the title compound (21.4 mg, 21% yield) as a white solid. LCMS: m/z＝883.5[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ10.9 (s, 1H), 8.76 (s, 1H), 8.10 (s, 2H), 7.05-6.68 (m, 4H), 5.69 (s, 1H), 5.32 (dd, J＝12.6, 5.4Hz, 1H), 4.49-3.83(m,5H),3.60-3.49(m,16H),3.46(t,J＝6.0Hz,2H),3.15-3.02(m,1H),3.01-2.78(m,4H),2.75-2.59(m,3H),2.07-1.42(m,12H),1.26(s,3 H).

Table 5. Compounds synthesized by coupling the corresponding amine with an acid by method 2.

^a Coupling was performed using standard conditions and the coupled product was purified via standard techniques including prep-HPLC and reverse phase chromatography. b Coupling was performed using CMPI, DIEA in DMF at rt for 1.5 hr.

Example 3 (Method 3): Synthesis of [(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-[7-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]heptyl]carbamate (I-81)

Step 1-[(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-[9-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]nonyl]carbamate. A solution of 5-(7-aminoheptyl)-3-methyl-2-oxo-benzoimidazol-1-yl)-1H-pyrazol-3-yl)cyclopentylphenyl ester (50 mg, 101 μmol, intermediate P), 3-[5-(7-aminoheptyl)-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (56.4 mg, 151 μmol, intermediate BT) and DIEA (65.2 mg, 504 μmol) in DMF (0.5 mL) was stirred at 80 °C for 12 h. After completion, the mixture was quenched with sat. NH ₄ Cl (5 mL) and extracted with EtOAc (5 mL×2). The combined organic layers were washed with brine (10 mL×2), dried over Na ₂ SO ₄ , and concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=0/1) to give the title compound (0.04 g, 21% yield, 40% purity) as an orange solid. LCMS: tR=0.680min., (ES ⁺ )m/z (M+H) ⁺ =774.4.

Step 2-[(1R,3S)-3-[1-tert-butyl-5-[[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-[7-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]heptyl]carbamate. A solution of [[5-(methoxymethyl)-2-methyl-pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-[7-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]heptyl]carbamate (0.03 g, 38.8 μmol, 40% purity) in HCOOH (1 mL) was stirred at 80 ° C for 2 h. After completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA conditions, column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 35%-65%, 10 min) to give the title compound (15 mg, 20.3 μmol, 52% yield) as a white solid. LCMS: tR＝0.620min., (ES ⁺ )m/z(M+H) ⁺ =718.3. ¹ H NMR (400MHz, DMSO-d6)δ＝12.41-12.09(br,1H),11.07(s,1H),10.90-10.56(br,1H),7.11(s,1H),7.04-6.99 (m,2H),6.97(s,1H),6.84(br d,J＝8.8Hz,1H),6.40(brs,1H),5.32(br dd,J＝5.2,12.4Hz,1H),5.02-4.94(m,1H),4.33(s,2H),4.04(s,3H),3.31(br s,3H),3.26(s,3H),3.10-3.04(m,1H),2.96-2.87(m,3H),2.71-2.66(m,1H),2.66-2.55(m,4H),2.54(br s,1H),2.03-1.97(m,2H),1.89(br dd,J＝3 .6,6.4Hz,1H),1.77-1.69(m,2H),1.57(br s,2H),1.40-1.34(m,2H),1.25(br d,J＝13.2Hz,6H).

Table 6. Compounds synthesized by coupling the corresponding amine with the carbamate in step 1 by method 3.

^a Step 1 is operated at any temperature between 60-80°C for 12-27 hrs. Step 2 is operated at any temperature between 70-80°C for 2-24 hrs.

Example 4 (Method 4): Synthesis of (1R,3S)-3-(5-(1-(4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-84)

Step 1-(1R,3S)-3-(1-(tert-butyl)-5-(1-((1r,4S)-4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To the mixture was added [4-[4- To a solution of [[2-tert-butyl-5-[(1S,3R)-3-(isopropylcarbamoyloxy)cyclopentyl]pyrazol-3-yl]carbamoyl]pyrazol-1-yl]cyclohexyl]methyl ester (40.0 mg, 67.5 μmol, Intermediate R) and 3-[3-methyl-4-[[4-(methylamino)-1-piperidinyl]methyl]-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (78.0 mg, 202.44 μmol, Intermediate S) in DMF (1 mL) was added Cs ₂ CO ₃ (110 mg, 337 μmol). The reaction was then stirred at 20-60° C. under nitrogen atmosphere for 10 h. After completion, the reaction was filtered to obtain a filtrate. The filtrate was purified by prep-HPLC (0.1% FA condition) to give the title compound (10 mg, 17% yield) as a colorless oil. LC-MS (ESI ⁺ ) m/z 882.5 (M+H) ⁺ .

Step 2-(1R,3S)-3-(5-(1-(4-(((1-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)piperidin-4-yl)(methyl)amino)methyl)cyclohexyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. At 20° C., under a nitrogen stream, the mixture was stirred for 2 h. ,3S)-3-[2-tert-butyl-5-[[1-[4-[[[1-[[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]methyl]-4-piperidinyl]-methyl-amino]methyl]cyclohexyl]pyrazole-4-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (10.0mg, 11.3μmol) in formic acid (0.2mL). The reactant was then stirred at 70°C under a nitrogen atmosphere for 10h. After completion, the reactant was concentrated to give a residue. The residue was purified by prep-HPLC (0.1% FA condition) to give the title compound (5mg, 50% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 10.43-10.26 (br s, 1H), 8.37 (br d, J = 5.2Hz, 2H), 8.12-7.96 (m, 1H), 7.09-6.85 (m, 3H), 6.36 (s, 1H), 5.63-5.43 (m, 1H), 5.00 (br d,J＝4.0Hz,1H),4.29-3.98(m,2H),3.68-3.60(m,8H),3.11-2.93(m,3H),2.90-2.72(m,4H),2.65-2.55(m,1H),2.41-2.34(m,3H),2.17-1.54(m, 18H), 1.38-1.22 (m, 2H), 1.20-1.09 (m, 2H), 1.03 (br d, J = 6.4Hz, 6H). LC-MS(ESI ⁺ )m/z 826.3(M+H) ⁺ .

Table 7. Compounds synthesized by coupling the corresponding amine with the mesylate in step 1 via method 4.

^a K ₂ CO ₃ was used as base in step 1, which was run in MeCN at 40 °C for 2 hr. ^b Step 1 was run at 60 °C for 12 hr, step 2 was run at 75 °C for 12 hr.

Example 5 (Method 5): [(1R,3S)-3-[5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]-1H-pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (I-78)

Step 1-(1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To a solution of 5-[[2-[2-(2-prop-2-ynyloxyethoxy)ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (200 mg, 378 μmol, intermediate X) and 3-(4-bromo-3-methyl-2-oxo-benzoimidazol-1-yl)piperidine-2,6-dione (153 mg, 454 μmol, intermediate H) in THF (1 mL) and ACN (1 mL) were added XPhos Pd G3 (96.1 mg, 113 μmol) and Cs ₂ CO ₃ (616 mg, 1.89 mmol). The mixture was stirred at 60 °C under nitrogen atmosphere for 4 h. Upon completion, the reaction mixture was quenched with NH ₄ Cl (saturated aqueous solution, 5 mL) at 0 °C and then extracted with EtOAc (5 mL×3). The combined organic layers were washed with brine (5 mL x 3), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-68%, 10 min) to give the title compound (70 mg, 24% yield) as a white solid. LCMS: tR = 0.642 min., (ES+) m/z (M+H) + = 786.3.

Step 2-[(1R,3S)-3-[1-tert-butyl-5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate. A solution of 1-(tert-butyl)-5-(1-(2-(2-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)ethoxy)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (100 mg, 127 μmol) and _PtO2 (14.0 mg, 61.7 μmol) in THF (2 mL) was placed under _H2 atmosphere and stirred at 25 °C for 1 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (100 mg) as a brown solid.

Step 3-[(1R,3S)-3-[5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]-1H-pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate. A solution of 5-[[2-[2-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-4-yl]propoxy]ethoxy]ethyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (70 mg, 88.6 μmol) in HCOOH (1 mL) was stirred at 80 ° C for 2 h. After completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA conditions, column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 28%-58%, 10 min) to give the title compound (20 mg, 30% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.20 (br s, 1H), 11.08 (s, 1H), 10.73 (br s, 1H), 7.51 (d, J = 2.0Hz, 1H), 7.12 (d, J = 1.6Hz, 1H), 6.95 (br d, J = 5.2Hz, 3H), 6.85-6. 81(m,1H),6.41(br s,1H),5.35(br dd,J＝5.2,12.5Hz,1H),5.04-4.95(m,1H),4.70(t,J＝5.6Hz,2H),3.76(t,J＝5.6Hz,2H),3.61-3.54(m,1H),3.52(s,3H),3.50-3.42(m,4H),3.38(br t, J＝6.0Hz,2H),3.09-3.00(m,1H),2.92-2.87(m,2H),2.85(br d,J＝5.6Hz,1H),2.75-2.61(m,2H),2.46-2.41(m,1H),2.04-1.96(m,2H),1.91-1.84(m,1H),1.80-1.70(m,4H),1.64-1.57(m,1H),1.02(d,J＝6.4 Hz, 6H); LC-MS (ESI ⁺ )m/z734.3(M+H) ⁺ .

Table 8. Compounds synthesized by coupling the corresponding alkyne with the bromide in step 1 via method 5.

^a Step 1 was run at 60°C for 4-12 hr. Step 3 was run at 70-80°C for 2-12 hr. Purification was performed by standard techniques including prep HPLC with various conditions. ^b Step 2 utilized Pd/C and hydrogenation (15 psi) was performed in THF at rt for 10 min-12 hr. ^c Chloride (not bromide) was used for Step 1. ^d Step 2 hydrogenation was skipped. ^e Step 1 was coupled using CuI, Pd(PPh ₃ ) ₂ Cl ₂ and TEA and the mixture was stirred at 60°C for 2 hours.

Example 6 (Method 6): Synthesis of (1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (I-247)

Step 1-(1R,3S)-3-(1-(tert-butyl)-3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To 2-[1-[7-[1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. To a solution of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (26 mg, 0.08 mmol, Intermediate U) in DMF (1 mL) was added HATU (40 mg, 0.11 mmol) followed by DIEA (27 mg, 0.21 mmol). The mixture was stirred at 50 °C for 5 h. Upon completion, HCOOH (0.2 mL) was added to the mixture and the mixture was stirred at 20 °C for 0.5 h. The solution was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 38%-68%, 11.5 min) and lyophilized to give the title compound (25 mg, 46% yield) as a yellow solid. LC-MS (ESI ⁺ ) m/z 772.7 (M+H) ⁺ .

Step 2-isopropylcarbamic acid (1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl ester. A solution of (2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl ester (25 mg, 0.03 mmol) in HCOOH (2.00 g, 41.63 mmol) was stirred at 80° C. for 12 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 11.5 min) and lyophilized to give the title compound (3 mg, 11% yield) as a yellow gum. LC-MS(ESI ⁺ )m/z 716.6(M+H) ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.11-11.95 (m, 1H), 11.09 (br s, 1H), 10.34 (d, J = 3.2Hz, 1H), 7.56 (s, 1H), 7.30 (s, 1H), 6.99-6.90 (m, 3H), 6.88-6.83 (m, 1H ),6.37-6.21(m,1H),5.36(dd,J ₁ =12.4Hz,J ₂ ＝4.8Hz,1H),5.03-4.93(m,1H),4.03(t,J＝7.2Hz,2H),3.54(s,3H),3.39(s,2H),3.07-2.97(m,1H),2.91-2.82(m,3H),2.76-2.68(m,1H),2.66-2. 58(m,1H),2.04-1.96(m,2H),1.90-1.83(m,1H),1.77-1.67(m,4H),1.64-1.51(m,4H),1.41-1.29(m,5H),1.25-1.20(m,2H),1.02(d,J＝6.4Hz,6H) .

Example 7. Synthesis of (1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (I-103)

(1R,3S)-3-(3-(2-(1-(7-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate was synthesized as described in Method 6, coupled with 2-(1-(7 -(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)heptyl)-1H-pyrazol-4-yl)acetic acid (Intermediate AY) and (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (Intermediate U) in step 1. The final compound was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 11.5min) and lyophilized to give the title compound (11 mg, 34% yield) as a yellow gum. LC-MS (ESI ⁺ )m/z 716.6(M+H) ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ )δ=12.17-11.89(m,1H),11.08(s,1H),10.34(s,1H),7.56(s,1H),7.30(s,1H),7.03-6.97(m,2 H), 6.93 (d, J = 7.6Hz, 1H), 6.85 (dd, J ₁ = 8.0Hz, J ₂ = 1.2Hz, 1H), 6.28 (br s, 1H), 5.33 (dd, J ₁ = 12.8Hz, J ₂ ＝5.2Hz,1H),4.98(d,J＝2.0Hz,1H),4.02(t,J＝7.2Hz,2H),3.56(td,J ₁ ＝13.6Hz,J ₂ ＝6.8Hz,1H),3.39(s,2H),3.32(s,1H),3.09-2.97(m,1H),2.96-2.84(m,1H),2.77-2.66(m,1H),2.66-2.56(m,3H),2.49-2.39(m,2H),2.05-1.93( m,2H),1.92-1.81(m,1H),1.77-1.63(m,4H),1.62-1.51(m,3H),1.36-1.15(m,7H),1.02(d,J=6.4Hz,6H).

Example 8 (Method 7): Synthesis of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide (I-157)

To a solution of 4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-3-methyl-N-(3-piperazin-1-ylpropyl)benzenesulfonamide (50 mg, 77.1 μmol, TFA, intermediate DI) in DMF (2 mL) was added TEA (7.81 mg, 77.1 μmol). Then 3-[3-methyl-2-oxo-5-(4-oxo-1-piperidinyl)benzimidazol-1-yl]piperidine-2,6-dione (27.4 mg, 77.1 μmol, intermediate DH) and HOAc (4.63 mg, 77.1 μmol) were added at -10°C and the mixture was stirred for 30 min. Then, NaBH(OAc) ₃ (32.7 mg, 154 μmol) was added and the mixture was stirred at -10°C for 2 hr. After completion, the reaction mixture was quenched with water (0.05 mL) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Waters xbridge 150*25 mm 10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 27%-57%, 8 min) to give the title compound (3.9 mg, 6% yield) as a pale white solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.06(s,1H),9.65(s,1H),8.74(s,1H),8.16(s,1H),7.77(d,J＝7.2Hz,1H),7.68(s,1H),7.65-7.60(m,1H),7.56-7.50(m,1H),6.97-6.87(m,1H ),6.81(s,1H),6.61(d,J＝8.4Hz,1H),5.69-5.56(m,1H),5.28(dd,J＝4.4,13. 2Hz,1H),3.59(td,J＝4.0,6.4Hz,2H),2.87-2.74(m,4H),2.71-2.64(m,3H),2.63(s,2H),2.59(s,3H),2.34(s,6H),2.29-2.13(m,5H),2.04-1.92(m ,2H),1.88-1.75(m,2H),1.61-1.48(m,4H),1.41(d,J＝6.4Hz,6H), LC-MS(ESI ⁺ )m/z 874.3(M+H) ⁺ .

Table 9. Compounds synthesized by reductive amination of the corresponding amines and ketones/aldehydes by method 7.

^a Reductive amination was performed under standard conditions, including the use of KOAc as the base used, and the addition of The reaction was carried out at any temperature from -10 to rt, and the final product was purified by standard techniques including prep-HPCl and silica gel chromatography. ^b The product of the reductive amination was further hydrogenated over Pd/C and DIEA in THF under H ₂ (15 PSI) at rt for 12 hr.

Example 9. Synthesis of (1R,3S)-3-(5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-53)

Step 1-(1R,3S)-3-(1-(tert-butyl)-5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To 3-(4-(3,9-diazaspiro[5.5]undec-3-ylmethyl)-3-methyl-2-oxo-2,3 To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (45 mg, 88.8 μmol, intermediate BV) in DMF (1 mL) and THF (1 m) was added AcOH (16.0 mg, 266 μmol), NaBH(OAc) ₃ (37.6 mg, 177 μmol) and AcOK (26.1 mg, 266 μmol) in one portion. The mixture was stirred at 25 °C for 10 h. Upon completion, the resulting mixture was poured into ice water (3 mL) and extracted with ethyl acetate (2×3 mL). The combined organic phases were washed with brine (2×3 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC [column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 9%-39%, 10min] to give the title compound (10 mg, 10.9 μmol, 12% yield) as a yellow oil. LC-MS (ESI+) m/z 458.9 (M+H) ⁺ .

Step 2-(1R,3S)-3-(5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. (1R,3S)-3-(1-(tert- A solution of 5-(1-(4-((9-((1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)methyl)-3,9-diazaspiro[5.5]undec-3-yl)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl ester (10 mg, 10.9 μmol) in HCOOH (1 mL) was stirred at 20-80° C. for 1 h. After completion, the mixture was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 29%-59%, 10 min) to give the title compound (0.59 mg, 6% yield) as an off-white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ＝11.24-10.94 (m, 1H), 10.52 (br s, 1H), 9.08 (s, 1H), 8.30 (d, J＝3.6 Hz, 2H), 7.78 (d, J＝8.5 Hz, 2H), 7.43 (d, J＝8.4 Hz, 2H), 7.06 (br d,J＝7.5Hz,1H),7.00-6.90(m,2H),6.90-6.83(m,1H),6.46-6.37(m,1H),5.41-5.31(m,1H),5.05-4.95(m,1H),3.66(s,3H),3.63-3.55(m,4H),2 .94-2.83(m,2H),2.76-2.57(m,4H),2.37-2.32(m,8H),2.08-1.84(m,4H),1.80-1.56(m,4H),1.41(brd,J＝15.5Hz,6H),1.03(d,J＝6.6Hz,6H). LC-MS(ESI+)m/z 860.5(M+H) ⁺ .

Example 10. Synthesis of (1R,3S)-3-(3-(1-(4-(((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)(methyl)amino)methyl)phenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazole-5-yl)cyclopentyl isopropylcarbamate (I-54)

To a solution of 3-(3-methyl-4-(3-(methylamino)prop-1-yn-1-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (38.0 mg, 116 μmol, intermediate BY) in DMF (0.3 mL) and THF (0.3 mL) were added KOAc (30.5 mg, 310 μmol), (1R,3S)-3-(5-(1-(4-formylphenyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (35 mg, 77.7 μmol, intermediate BW) and NaBH(OAc) ₃ (32.9 mg, 155 μmol) in one portion at 0°C. The mixture was stirred at 0-25°C for 10 h. The mixture was poured into ice water (3 mL) and extracted with ethyl acetate (2×3 mL). The combined organic phase was washed with brine (2×3 mL) and then dried over sodium sulfate. The mixture was then filtered and the filtrate was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-45%, 10min) to give the title compound (8.17 mg, 10.7 μmol, 14% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ )δ=12.21-12.11(m,1H),11.12-11.08(m,1H),10.52(s,1H),9.11-9.07(m,1H),8.30(s,1H),7.83-7.81(m,2H),7.51-7.49(m) ,2H),7.17-6.95(m,4H),6.42(s,1H),5.42-5.36(m,1H),5.01-4.99(m,1H),3.69(s,3H),3.67 -3.60(m,4H),3.20-2.65(m,6H),2.33(s,3H),2.13(s,1H),2.04-1.72(m,6H),1.03(d,J＝6.4Hz,6H). LC-MS(ESI+)m/z 761.4(M+H) ⁺ .

Example 11. Synthesis of (1R,3S)-3-(5-(1-(2-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-56)

A solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(2-(4-(3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)piperazin-1-yl)ethyl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (25 mg, 30.8 μmol, synthesized via Step 1 of Method 5) in formic acid (0.5 mL) was stirred at 70 °C under nitrogen atmosphere for 10 h. After completion, the reaction was concentrated to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 11%-41%, 10 min) and lyophilized to give the title compound (1.56 mg, 7% yield) as a yellow gum. ¹ H NMR (400MHz, DMSO-d ₆ ) δ = 12.36-12.15 (m, 1H), 11.11 (br d, J = 4.8Hz, 1H), 10.75 (br s, 1H), 7.50 (d, J = 2.0Hz, 1H), 7.14 (d, J = 8.0Hz, 1H), 7.11-7.05 (m, 2H ),7.03-6.97(m,1H),6.94(br d,J＝6.8Hz,1H),6.44-6.36(m,1H),5.38(dd,J＝5.2,12.5Hz,1H),4.99(br d,J＝5.6Hz,1H),4.62(br t,J＝6.4Hz,2H),3.64-3.53(m,4H),3.49(s,2H),3.17-2.83(m,6H),2.77-2.56(m,6H),2.35-2.29(m,2H),2.06-1.97(m,2H),1.89(br d,J＝6.8Hz,5H ), 1.02 (d, J = 6.4Hz, 6H). LC-MS(ESI ⁺ )m/z 754.4(M+H) ⁺ .

Example 12. Synthesis of (1R,3S)-3-(5-(1-(9-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)non-8-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazole-3-yl)cyclopentyl isopropylcarbamate (I-86)

A solution of [(1R,3S)-3-[1-tert-butyl-5-[[2-[9-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzoimidazol-5-yl]non-8-ynyl]pyrazole-3-carbonyl]amino]pyrazol-3-yl]cyclopentyl]N-isopropylcarbamate (0.07 g, 89.5 μmol, synthesized via step 1 of method 5) in HCOOH (0.5 mL) was stirred at 80° C. for 2 h. After completion, the mixture was concentrated in vacuo and purified by prep-HPLC (FA conditions, column: 3-Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.225% FA)-ACN]; B%: 42%-72%, 10 min) to give the title compound (12 mg, 17% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ = 7.50 (d, J = 2.0Hz, 1H), 7.13 (br s, 1H), 7.11 (d, J = 8.0Hz, 1H), 7.06-7.03 (m, 1H), 6.99 (d, J = 8.0Hz, 1H), 6.97-6.92 (m, 1H), 6.42 ( br s,1H),5.39(dd,J＝5.2,12.8Hz,1H),5.03-4.97(m,1H),4.52(br t,J＝7.2Hz,2H),3.63(s,3H),3.58(br dd,J＝6.4,14.0Hz,1H),3.12-3.04(m,1H),2.93-2.84(m,1H),2.76-2.65(m,2H),2.35-2.31(m,1H),2.05-2.00(m,2H),1.89(dt,J＝2.8,6.8Hz,1H), 1.77-1.70(m,4H),1.67-1.61(m,1H),1.58-1.51(m,2H),1.41-1.23(m,7H),1.03(d,J＝6.5Hz,6H).

Example 13. Synthesis of (1R,3S)-3-(5-(1-(12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazole-3-yl)cyclopentyl isopropylcarbamate (I-88)

A solution of (1R,3S)-3-(1-(tert-butyl)-5-(1-(12-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)dodec-11-yn-1-yl)-1H-pyrazole-5-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (50 mg, 60.7 μmol, synthesized via step 1 of method 5) in HCOOH (2 mL) was stirred at 70° C. for 12 h. After completion, the mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 62%-92%, 11.5min) and lyophilized to give the title compound (12.7mg, 25% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d6) δ 12.23 (br s, 1H), 11.10 (br s, 1H), 10.69 (br s, 1H), 7.48 (s, 1H), 7.25-6.81 (m, 5H), 6.41 (br s, 1H), 5.38 (br dd, J=5.2, 12.6 Hz, 1H), 5.00 (br d, J=3.6 Hz, 1H), 4.49 (br t,J＝6.8Hz,2H),3.72-3.49(m,3H),3.14-3.02(m,1H),2.96-2.82(m,1H),2.77-2.57(m,2H),2.47-2.40(m,4H),2.08-1.96(m,3H),1.93-1.84(m, 1H),1.78-1.65(m,4H),1.60-1.51(m,2H),1.46-1.35(m,2H),1.34-1.17(m,10H),1.03(br d,J＝6.4Hz,6H). LC-MS(ESI+)m/z 768.4(M+H) ⁺ .

Example 14. Synthesis of (1R,3S)-3-(5-(1-(11-(3-(2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamino)acetyl)pyrrolidin-2-yl)thiazole-4-carbonyl)phenoxy)undecyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (I-148)

Step 1-((S)-1-(((S)-2-((S)-2-(4-(3-((11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate tert-butyl ester. To 4-methylbenzenesulfonic acid 11-(4-((1-(tert-butyl)-3-((1S,3R)-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamate was added. To a solution of ((S)-1-(((S)-1-cyclohexyl-2-((S)-2-(4-(3-hydroxybenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)amino)-1-oxopropan-2-yl)(methyl)carbamic acid tert-butyl ester (49.4 mg, 82.5 μmol, intermediate ER) in DMF (2 mL) was added KI (1.14 mg, 6.88 _μmol ) and _Cs2CO3 (67.2 mg, 206 μmol). The mixture was then stirred at 70 °C for 2 h. After completion, the reaction mixture was quenched with aqueous NaHCO ₃ solution (2 mL) at 20° C., then diluted with 1 mL of EtOAc and extracted with EtOAc (2 mL×3). The combined organic layers were washed with brine (2 mL×2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO ₂ , petroleum ether:ethyl acetate=0:1) to give the title compound (20 mg, 25% yield) as a brown solid.

Step 2-(1R,3S)-3-(5-(1-(11-(3-(2-((S)-1-((S)-2-cyclohexyl-2-((S)-2-(methylamino)propionylamino)acetyl)pyrrolidin-2-yl)thiazole-4-carbonyl)phenoxy)undecyl)-1H-pyrazole-4-carboxamido)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. To ((S)-1-(((S)-2-((S)-2-(4-(3-((11-(4-((1-(tert-butyl)-3-((1S,3R) To a solution of tert-butyl-3-((isopropylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamoyl)-1H-pyrazol-1-yl)undecyl)oxy)benzoyl)thiazol-2-yl)pyrrolidin-1-yl)-1-cyclohexyl-2-oxoethyl)amino)-1-oxopropan-2-yl)methyl)carbamate (20 mg, 17.3 μmol) in DCE (0.5 mL) was added TFA (154 mg, 1.35 mmol, 0.1 mL) and the mixture was then stirred at 80 °C for 12 h. After completion, filtration and concentration under reduced pressure gave a residue, which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10μm; mobile phase: [water (0.225% FA)-ACN]; B%: 34%-64%, 10 min) to give the title compound (3.89 mg, 23% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d6) δ=12.32-11.83(m,1H),10.33(br s,1H),8.51-8.43(m,1H),8.33(s,1H),8.03(s,1H),7.98-7.88(m,1H),7.68-7.58(m,2H),7. 48-7.42(m,1H),7.25-7.19(m,1H),6.95(br d,J＝6.8Hz,1H),6.36(br s,1H),5.42-5.34(m,1H),4.99(br d,J＝2.8Hz,1H),4.52-4.42(m,1H),4.10(t,J＝6.8Hz,2H),4.01(brt,J＝6.4Hz,3H),3.84-3.76(m,1H),3.71-3.63(m,1H),3.55(br dd,J＝7.6,14.0Hz,2H) ,3.09-2.99(m,2H),2.99-2.92(m,1H),2.29-2.23(m,1H),2.22-2.12(m,3H),2.09(s,2H),2.05-1.96(m,3H),1.92-1.85(m,1H),1.73(br dd,J＝6.4,13.1Hz,8H),1.60(br s,4H),1.55-1.48(m,1H),1.45-1.38(m,2H),1.24(br s,10H),1.20-1.12(m,3H),1.11-1.05(m,4H),1.02(br d,J＝6. 4Hz,6H),0.96-0.89(m,1H). LC-MS(ESI+)m/z 997.6(M+H) ⁺ .

Example 15. Synthesis of 4-[[5-amino-1-(3-methylthiophene-2-carbonyl)-1,2,4-triazol-3-yl]amino]-N-[2-[[1-[2-[3-[1-(2,6-dioxo-3-piperidinyl)-3-methyl-2-oxo-benzimidazol-5-yl]propoxy]ethyl]triazol-4-yl]methoxy]ethyl]benzenesulfonamide (I-136)

To a solution of 3-[5-[3-(2-azidoethoxy)propyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (70 mg, 200 μmol, intermediate FD) and 4-[[5-amino-1-(3-methylthiophene-2-carbonyl)-1,2,4-triazol-3-yl]amino]-N-(2-prop-2-ynyloxyethyl)benzenesulfonamide (83.4 mg, 181 μmol, intermediate EE) in DMF (1 mL) at 20 °C under a stream of nitrogen was added _CuSO4 (14.5 mg, 90.6 μmol), sodium (2R)-2-[(2R)-3,4-dihydroxy-5-oxo-2H-furan-2-yl]-2-hydroxy-ethoxide (108 mg, 543 μmol, VCNa), t-BuOH (0.9 mL) and _H2SO4 . The reaction mixture was stirred at 70 ° C for 2 h under a nitrogen atmosphere. After completion, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase HPLC (column: Phenomenex Luna C18 100*30mm*5μm; mobile phase: [water (0.225% FA)-ACN]; B%: 30%-60%, 8min) to give the title compound (58 mg, 37% yield) as a white solid. ¹ H NMR (400MHz, DMSO-d6) δ＝11.08(br s,1H),9.94(s,1H),8.06-8.02(m,2H),7.91-7.79(m,4H),7.76-7.70(m,2H),7.51-7.43(m,1H),7.16(d,J＝5.2Hz,1 H),7.01-6.91(m,2H),6.79(dd,J＝1.6,8.0Hz,1H),5.33(dd,J＝5.2,12.8Hz,1H),4.54-4.49(m,2H),4.47(s,2H),3.75(t,J＝5.2Hz,2H),3.45-3.40(m,2H ),3.38(br s,4H),3.31(s,3H),2.91-2.86(m,2H),2.76-2.65(m,1H),2.63(s,3H),2.57-2.52(m,2H),2.04-1.95(m,1H),1.81-1.68(m,2H); LC-MS(ESI+)m/z 84 7.4(M+H) ⁺ .

Example 16. Synthesis of 3-[4-[7-[4-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-1-piperidinyl]sulfonyl]pyrazol-1-yl]heptylamino]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione (I-165)

Step 1 - 3-[4-(7-bromoheptylamino)-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione. To a solution of 3-[4-(7-bromoheptylamino)-3-methyl-2-oxo-benzimidazol-1-yl]-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (24.0 mg, 41.9 μmol, Intermediate JZ) and 6-chloro-8-isopropyl-2-[[1-(1H-pyrazol-4-ylsulfonyl)-4-piperidinyl]amino]pyrido[2,3-d]pyrimidin-7-one (18.9 mg, 41.9 μmol, Intermediate KB) in DMF (2 mL) was added _{K2CO3 .} (29.0 mg, 209 μmol) and KI (6.97 mg, 41.9 μmol). The mixture was stirred at 25 °C for 2 hr. Upon completion, the reaction mixture was quenched with H ₂ O (1 mL) at 25 °C. The mixture was then filtered and partitioned between EA (10 mL) and water (10 mL). The organic layer was collected, and the aqueous layer was extracted with EA (2×8 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (35 mg, 88% yield) as a white solid. LCMS (ESI ⁺ ) m/z 942.5 (M+H) ⁺ .

Step 2-3-[4-[7-[4-[[4-[(6-chloro-8-isopropyl-7-oxo-pyrido[2,3-d]pyrimidin-2-yl)amino]-1-piperidinyl]sulfonyl]pyrazol-1-yl]heptylamino]-3-methyl-2-oxo-benzoimidazol-1-yl]piperidine-2,6-dione. To a solution of 3-(4-methoxyphenyl)-1-piperidin-2-yl)-2-nitropropene (30.0 mg, 31.8 μmol) in TFA (1.6 mL) was added TfOH (0.2 mL). The mixture was stirred at 70 °C for 2 hr. After completion, the mixture was concentrated in vacuo to give a residue. ACN (1 mL) and TEA were added to the residue at 25 °C until pH = 6. The mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenexluna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; B%: 45%-75%, 9 min) to give the title compound (19.2 mg, 69% yield) as a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ )δ11.06(s,1H),8.57(s,1H),8.45-8.36(m,1H),8.11-7.74(m,3H),6.84(t,J＝8.0Hz,1H),6.50(d,J＝7.6Hz,1H),6.38(d,J＝8.4Hz,1H),5.83-5.58(m ,1H),5.28(dd,J＝5.2,12.4Hz,1H),4.20(t,J＝6.8Hz,2H),3.89-3.67(m,2H),3.59(s,3H) ,3.01(t,J＝7.2Hz,2H),2.94-2.82(m,1H),2.75-2.67(m,1H),2.66-2.58(m,2H),2.46(s,2H),2.40(d,J＝12.4Hz,1H),2.02-1.91(m,3H),1.87-1.7 9(m,2H),1.73-1.53(m,5H),1.48(d,J＝6.8Hz,6H),1.35(d,J＝2.4Hz,4H),1.25-1.19(m,2H). LCMS(ESI ⁺ )m/z 822.4(M+H) ⁺ .

Example 17. Degradation analysis

CDK2 and CDK1 degradation by immunoblotting

Ovarian cancer cell line OVCAR-8 was cultured in complete growth medium in a 12-well dish. Serial dilutions of each compound were added to each well from a 2X stock solution, and the cells were cultured for 24 hours. Cells were collected by centrifugation, and frozen RIPA buffer supplemented with protease/phosphatase inhibitors was added to lyse the cell pellet, then incubated on ice for 20 minutes. The lysate was clarified by centrifugation, and 5X SDS loading buffer was added to the supernatant, then heated to 100°C for 10 minutes. Aliquots of the samples were separated by SDS-PAGE and transferred to nitrocellulose membranes. Immunoblots were performed according to standard procedures using an anti-CDK2 primary antibody (Abcam ab32147) at a dilution of 1:1000 and an IRDye 800CW goat anti-rabbit secondary antibody (LICOR), and imaged using a LICOR Odyssey instrument. The dots were stained with an anti-β-actin primary antibody (Cell Signaling Technology mAb#4970) for normalization. Normalized CDK2/actin values were calculated as a percentage of DMSO treated cells and plotted to determine the concentration at which the CDK2 signal was reduced by 50% (DC50).CDK1 degradation was determined similarly using an anti-CDK1 primary antibody (Abcam ab131450).

CCNE1 degradation in MKN-1 cells

Gastric cancer cell line MKN-1 was cultured in complete growth medium in a 6-well dish. Serial dilutions of each compound were added to each well from a 2X stock solution, and the cells were cultured for 24 hours. After 24 hours of incubation, cells were lysed by adding frozen RIPA buffer supplemented with protease/phosphatase inhibitors and incubated on ice for 20 minutes. The lysate was clarified by centrifugation, and 5X SDS loading buffer was added to the supernatant, which was then heated to 100°C for 10 minutes. Aliquots of the samples were separated by SDS-PAGE and transferred to nitrocellulose membranes. Immunoblots were performed according to standard procedures using an anti-CCNE1 primary antibody (Abcam #ab33911) at a dilution of 1:1000 and an IRDye 800CW goat anti-rabbit secondary antibody (LICOR), and imaged using a LICOROdyssey instrument. The dots were stained with an anti-β-actin primary antibody (Cell Signaling Technology mAb #3700) for normalization. Normalized CCNE1/actin values were calculated as a percentage of DMSO-treated cells and plotted to determine the concentration that reduced CCNE1 signal by 50%.

The DC50 results of the compounds of the invention for CDK2, CDK1 and CCNE1 are reported in Table 10. The letter codes for DC50 and IC50 include: A (<0.01 μM), B (0.01-0.1 μM), C (>0.1-1.0 μM), D (>1.0-5.0 μM) and E (>5.0 μM).

Table 10.

******

Although a number of embodiments of the present invention have been described, it is apparent that our basic examples can be altered to provide other embodiments utilizing the compounds and methods of the present invention. It should therefore be understood that the scope of the invention should be defined by the appended claims rather than by the specific embodiments presented by way of example.

Claims (28)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: CBM is a CDK binding portion capable of binding to CDK2 protein, and the compound of formula I is a compound of formula I-a: or a pharmaceutically acceptable salt thereof, wherein: R ^a and R ^b are independently hydrogen or R ^A , or ^Ra and ^Rb together with the nitrogen to which they are attached form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached; each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W, Ring X and Ring Y are independently selected from the following rings: phenyl, 4-7 membered saturated or partially unsaturated carbocyclic group or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Z is a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen optionally form together with their intervening atoms a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached; ^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-; v is 0 or 1; w, x, y and z are independently 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by the following groups: -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, in: each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclylene, 4-11 membered saturated or partially unsaturated spirocarbocyclylene, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and DIM is a degradation inducing moiety, wherein DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. 2. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: CBM is a CDK binding portion capable of binding to CDK2 protein, and the compound of formula I is a compound of formula I-b: or a pharmaceutically acceptable salt thereof, wherein: Ring W and Ring X are independently a fused ring selected from the following: benzo, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from the following: phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Z is a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; or Two R ^w groups attached to the same carbon atom optionally together form a spiro-fused ring selected from: 3-5 membered saturated or partially unsaturated carbocyclyl and 3-5 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and ^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-; v is 0 or 1; w, x, y and z are independently 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by the following groups: -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, in: each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclylene, 4-11 membered saturated or partially unsaturated spirocarbocyclylene, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and DIM is a degradation inducing moiety, wherein DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. 3. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: CBM is a CDK binding portion capable of binding to CDK2 protein, and the compound of formula I is a compound of formula I-c: or a pharmaceutically acceptable salt thereof, wherein: Ring W, Ring X and Ring Y are independently selected from the following rings: phenyl, 4-7 membered saturated or partially unsaturated carbocyclic group or heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Z is phenyl, or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group, or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen optionally form together with their intervening atoms a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached; ^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-; v is 0 or 1; w, x, y and z are independently 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by the following groups: -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, in: each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclylene, 4-11 membered saturated or partially unsaturated spirocarbocyclylene, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and DIM is a degradation inducing moiety, wherein DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. 4. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: CBM is a CDK binding portion capable of binding to CDK2 protein, and the compound of formula I is a compound of formula I-d: or a pharmaceutically acceptable salt thereof, wherein: R ^a and R ^b are independently hydrogen or R ^A , or ^Ra and ^Rb together with the nitrogen to which they are attached form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached; each ^RA is independently an optionally substituted group selected from the group consisting of a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring, or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring W is a ring selected from the following: phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring X is a bicyclic ring selected from naphthyl, a 9- to 10-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 9- to 10-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ^w , R ^x and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S (O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC(O) R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O) (OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O) ₂ R ,-NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic group, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic ring or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen optionally form together with their intervening atoms a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen atom to which they are attached; ^Lx is a covalent bond or a _C1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, -CF2-, -CRF-, -NR-, -S-, -S(O)-, -S(O) _{2- ,} or -CR=CR-; v is 0 or 1; w, x and z are independently 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by the following groups: -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, in: Each -Cy- is independently an optionally substituted bivalent ring selected from the group consisting of phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclylene, 4-11 membered saturated or partially unsaturated spirocarbocyclylene, 8-10 membered bicyclic arylene, a 4-7-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 4-11-membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10-membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and an 8-10-membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and DIM is a degradation inducing moiety, wherein DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. 5. A compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: CBM is a CDK binding portion capable of binding to CDK2 protein, and the compound of formula I is a compound of formula I-e: or a pharmaceutically acceptable salt thereof, wherein: Ring W and Ring X are independently a ring selected from the following: phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Y is a ring selected from the following: phenyl, a 4- to 7-membered saturated or partially unsaturated carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5- to 6-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring Z is phenyl or a 4- to 8-membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic group or a heterocyclic group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ^w , R ^x , ^Ry and R ^z are independently selected from hydrogen, ^RA , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)NROR, -CR ₂ NRC (O)R, -CR ₂ NRC(O)NR ₂ , -OC(O)R, -OC(O)NR ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP (O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -NRC(O)OR, -NRC(O)R, -NRC(O)N(R) ₂ , -NRS(O ) ₂ R, -NP(O)R ₂ , -NRP(O)(OR) ₂ , -NRP(O)(OR)NR ₂ , -NRP(O)(NR ₂ ) ₂ and -NRS(O) ₂ R; or Two R ^w groups attached to the same carbon atom optionally together form a spiro-fused ring selected from: 3-5 membered saturated or partially unsaturated carbocyclyl and 3-5 membered saturated or partially unsaturated heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; each ^RA is independently an optionally substituted group selected from: a _C1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen atom to which they are attached, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and ^Lx and ^Ly are independently a covalent bond or a _C1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by -O-, -C(O)-, -C(S)-, _-CF2- , -CRF-, -NR-, -S-, -S(O)-, -S(O) _2- , or -CR=CR-; v is 0 or 1; w, x, y and z are independently 0, 1, 2, 3 or 4; L is a covalent bond or a divalent saturated or partially unsaturated linear or branched C _1-50 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by the following groups: -Cy-, -O-, -NR-, -SiR ₂ -, -Si(OH)R-, -Si(OH) ₂ -, -P(O)OR-, -P(O)R-, -P(O)NR ₂ -, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) ₂ -, -NRS(O) ₂ -, -S(O) ₂ NR-, -NRC(O)-, -C(O)NR-, -OC(O)NR-, -NRC(O)O-, in: each -Cy- is independently an optionally substituted bivalent ring selected from phenylene, 8-10 membered bicyclic arylene, 4-7 membered saturated or partially unsaturated carbocyclylene, 4-11 membered saturated or partially unsaturated spirocarbocyclylene, 8-10 membered bicyclic saturated or partially unsaturated carbocyclylene, 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 4-11 membered saturated or partially unsaturated spiroheterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 8-10 membered bicyclic saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 8-10 membered bicyclic heteroarylene having 1-5 heteroatoms independently selected from nitrogen, oxygen and sulfur, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and DIM is a degradation inducing moiety, wherein DIM is a ligase binding moiety (LBM), a lysine mimetic, or a hydrogen atom. 6. The compound of any one of claims 1 to 5, wherein LBM is a celebron E3 ubiquitin ligase binding moiety, a VHL E3 ubiquitin ligase binding moiety, an IAP E3 ubiquitin ligase binding moiety, or a MDM2 E3 ubiquitin ligase binding moiety. 7. The compound of claim 6, wherein LBM is a celebron E3 ubiquitin ligase binding moiety, and the compound is of formula I-nn-1: or a pharmaceutically acceptable salt thereof, wherein: X ¹ , X ² and X ³ are each independently a divalent moiety selected from the group consisting of a covalent bond, -CH ₂ -, -C(O)-, -C(S)- or R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , or an optionally substituted C _1-4 aliphatic group; Each R ² is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R; Ring A is a condensed ring selected from the following: a 6-membered aryl group containing 0-2 nitrogen atoms, a 5- to 7-membered partially saturated carbocyclic group, a 5- to 7-membered partially saturated heterocyclic group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur; m is 0, 1, 2, 3 or 4; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 8. The compound of claim 6, wherein LBM is a celebron E3 ubiquitin ligase binding moiety and the compound is of formula I-aa: or a pharmaceutically acceptable salt thereof, wherein: ^X1 is a divalent moiety selected from the group consisting of a covalent bond, _-CH2- , _-CHCF3- , _-SO2- , -S(O)-, -P(O)R-, -P(O)OR-, -P(O) _NR2- , -C(O)-, -C(S)- or ^X2 is a carbon atom or a silicon atom; X ³ is a divalent moiety selected from: -CR ₂ -, -NR-, -O-, -S- or -SiR ₂ -; Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen optionally take together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R ¹ is hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH) ₂ R, -Si(OH)R ₂ , -SiR ₃ or an optionally substituted C _1-4 aliphatic group; Each R ² is independently hydrogen, R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -N(R) ₂ , -Si(R) ₃ , -S(O) ₂ R, - S(O) ₂ N(R) ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)N(R) ₂ , -C(O)N( R)OR, -C(R) ₂ N(R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC( O)N(R) ₂ , -OP(O)R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)(NR ₂ ), -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)N(R) ₂ , -N(R)S(O) ₂ R , -NP(O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)(NR ₂ ), -N(R)P(O)( NR ₂ ) ₂ or -N(R)S(O) ₂ R; Ring A is a bicyclic or tricyclic ring selected from the following: in Ring B is a fused ring selected from the following: a 6-membered aryl group, a 6-membered heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclyl group, a 5- to 7-membered saturated or partially unsaturated heterocyclyl ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; ^R3 is selected from hydrogen, halogen, -OR, -N(R) ₂ or -SR; Each R ⁴ is independently hydrogen, -R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ or -N(R)S(O) ₂ R; R ⁵ is hydrogen, C _1-4 aliphatic or -CN; each R ⁶ is independently an optionally substituted group selected from the following: a C _1-6 aliphatic group, a phenyl group, a 3-7 membered saturated or partially unsaturated carbocyclic ring or a heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L ¹ is a covalent bond or a C _1-3 divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S(O) ₂ -, or -(C)=CH-; and m is 0, 1, 2, 3 or 4. 9. The compound according to claim 8, wherein the compound is a compound of any one of the following formulae: or a pharmaceutically acceptable salt thereof. 10. The compound of claim 6, wherein LBM is a celebron E3 ubiquitin ligase binding moiety and the compound is in the formula I-nn: or a pharmaceutically acceptable salt thereof, wherein: Ring M is selected from X ¹ , X ⁶ and X ⁷ are each independently a divalent moiety selected from the group consisting of a covalent bond, -CH ₂ -, -CHCF ₃ -, -SO ₂ -, -S(O)-, -P(O)R-, -P(O)OR-, -P(O)NR ₂ -, -C(O)-, -C(S)- or X ³ and X ⁵ are each independently a divalent moiety selected from the group consisting of a covalent bond, -CR ₂ -, -NR-, -O-, -S- or -SiR ₂ -; ^X4 is a trivalent moiety selected from: Each R is independently hydrogen or an optionally substituted group selected from the following: _C1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen together with their intervening atoms form a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; Each R ^3a is independently hydrogen, R ⁶ , halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -SiR ₃ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(O)N(R)OR, -C(R) ₂ N( R)C(O)R, -C(R) ₂ N(R)C(O)N(R) ₂ , -OC(O)R, -OC(O)N(R) ₂ , -OP(O )R ₂ , -OP(O)(OR) ₂ , -OP(O)(OR)NR ₂ , -OP(O)(NR ₂ ) ₂ -, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ₂ , -N(R)S(O) ₂ R, -NP (O)R ₂ , -N(R)P(O)(OR) ₂ , -N(R)P(O)(OR)NR ₂ , -N(R)P(O)(NR ₂ ) ₂ or -N(R)S(O) ₂ R; each R ⁶ is independently an optionally substituted group selected from the group consisting of a C _1-6 aliphatic group, a phenyl group, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R ⁷ is independently hydrogen, halogen, -CN, -OR, -SR, -S(O)R, -S(O) ₂ R, -NR ₂ , -P(O)(OR) ₂ , -P(O)(NR ₂ )OR, -P(O)(NR ₂ ) ₂ , -Si(OH)R ₂ , -Si(OH) ₂ R, -SiR ₃ , or optionally substituted C _1-4 aliphatic; or ^R7 and ^X1 or ^X3 together with their intervening atoms form a 5-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Two ^R7 groups on the same carbon optionally form, together with their intervening atoms, a 3-6 membered spiro-fused ring or a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Two ^R groups on adjacent carbon atoms optionally form, together with their intervening atoms, a 3-7 membered saturated, partially unsaturated carbocyclic ring or a heterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur, or a 7-13 membered saturated, partially unsaturated bridged heterocyclic ring or a spiroheterocyclic ring having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon or sulfur; Ring D is selected from a 6- to 10-membered aryl group or a heteroaryl group containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5- to 7-membered saturated or partially unsaturated carbocyclic group, a 5- to 7-membered saturated or partially unsaturated heterocyclic group having 1-3 heteroatoms independently selected from boron, nitrogen, oxygen, silicon and sulfur, or a 5-membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; L ¹ is a covalent bond or a C _1-3 divalent straight or branched saturated or unsaturated hydrocarbon chain, wherein 1-2 methylene units of the chain are independently and optionally replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R) ₂ -, -CH(R)-, -C(F) ₂ -, -N(R)-, -S-, -S(O) ₂ - or -(C)=CH-; n is 0, 1, 2, 3 or 4; and q is 0, 1, 2, 3 or 4. 11. The compound according to claim 10, wherein the compound is a compound of any one of the following formulae: or a pharmaceutically acceptable salt thereof. 12. The compound according to claim 6, wherein LBM is a VHL E3 ubiquitin ligase binding moiety and the compound is selected from any one of the following formulae: (i) or a pharmaceutically acceptable salt thereof, wherein the variables R ¹ , R ² , R ³ , X and Y are each as defined and described in WO 2019/084026; (ii) or a pharmaceutically acceptable salt thereof, wherein the variables R ¹ , R ³ and Y are each as defined and described in WO 2019/084030; (iii) or a pharmaceutically acceptable salt thereof, wherein the variables R ¹ ′, R ² ′, R ³ ′, X and X′ are each as defined and described in WO 2013/106643 and US2014/0356322; (iv) or a pharmaceutically acceptable salt thereof, wherein the variables R ^{1 '} , R ^2' , R ^3' , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R _{1 1} , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₂₃ , R ₂₅ , E, G, M, X, X', Y, Z ₁ , Z ₂ , Z ₃ , Z ₄ and o are each as defined and described in WO 2016/149668 and US 2016/0272639; and (v) or a pharmaceutically acceptable salt thereof, wherein the variables R ^p , R ₉ , R ₁₀ , R ₁₁ , R _14a , R _14b , R ₁₅ , R ₁₆ , W ³ , W ⁴ , W ⁵ , X ¹ , X ² and o are each as defined and described in WO 2016/118666 and US 2016/0214972. 13. The compound according to claim 6 or 12, wherein the VHL E3 ubiquitin ligase binding moiety is selected from and 14. The compound according to claim 6, wherein LBM is an IAP E3 ubiquitin ligase binding moiety and the compound is selected from any one of the following formulae: (i) or a pharmaceutically acceptable salt thereof, wherein the variables R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each as defined and described in WO 2017/011590 and US2007/037004; and (ii) or a pharmaceutically acceptable salt thereof, wherein the variables W, Y, Z, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each as described and defined in WO 2014/044622, US 2015/0225449, WO 2015/071393 and US 2016/0272596. 15. The compound according to claim 6 or 14, wherein the IAP E3 ubiquitin ligase binding moiety is selected from and 16. The compound of claim 6, wherein LBM is a MDM2 E3 ubiquitin ligase binding moiety and the compound is selected from any one of the following formulae: (i) or a pharmaceutically acceptable salt thereof, wherein the variables R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₆ , R ₁₇ , R ₁₈ , R ₁₉ , R ₂₀ , R ₂₁ , R ₂₂ , R ₂₃ , R ₂₄ , R ₂₅ , R ₂₆ , R ₂₇ , R ₂₈ , R _{1 '} , R _2' , R _3' , R _4' , R _5' , R _6' , R _7' , R _8' , R _9' , R _10' , R _11' , R _12' , R _A , A', A", X, Y and Z are each as defined and described in WO 2017/011371 and US 2017/008904; and (ii) or a pharmaceutically acceptable salt thereof, wherein the variables R ^12c , R ^12d , R ¹³ , R ¹⁷ , R ^18b , R ^18c , R ^18d , A ⁵ , A ⁶ , A ⁷ , Q ¹ and Ar are each as defined and described in WO 2017/176957 and US 2019/127387. 17. The compound of claim 6 or 16, wherein the MDM2 E3 ubiquitin ligase binding moiety is selected from and 18. The compound according to any one of claims 1 to 17, wherein L is a covalent bond or a divalent saturated or partially unsaturated linear or branched _C1-20 hydrocarbon chain, wherein 0-6 methylene units of L are independently replaced by the following groups: -Cy-, -O-, -NR-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O) _2- , -N(R)S(O) _2- , -S(O) _2N (R)-, -N(R)C(O)-, -C(O)N(R)-, -OC(O)N(R)-, -N(R)C(O)O-. 19. The compound according to any one of claims 1 to 18, wherein the compound is selected from any one of the compounds depicted in Table 1 or a pharmaceutically acceptable salt thereof. 20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable carrier, adjuvant or vehicle. 21. The pharmaceutical composition of claim 20, further comprising another therapeutic agent. 22. A method of inhibiting or degrading CDK2 in a patient or a biological sample, comprising administering to the patient or contacting the biological sample with a compound according to any one of claims 1 to 19 or a pharmaceutical composition thereof. 23. A method of treating a CDK2-mediated disorder, disease or condition in a patient, comprising administering to the patient a compound according to any one of claims 1 to 19 or a pharmaceutical composition thereof. 24. The method of claim 23, wherein the CDK2-mediated disorder, disease or condition is cancer. 25. The method of claim 24, wherein the cancer is characterized by amplification or overexpression of CCNE1. 26. Use of a compound according to any one of claims 1 to 19, or a pharmaceutical composition thereof, for the manufacture of a medicament for use in a method of treating a CDK2-mediated disorder, disease or condition in a patient, the method comprising administering the compound or composition to the patient. 27. The use according to claim 26, wherein the CDK2-mediated disorder, disease or condition is cancer. 28. The use according to claim 27, wherein the cancer is characterized by amplification or overexpression of CCNE1.